Tiqing Liu - Academia.edu (original) (raw)

Papers by Tiqing Liu

Research paper thumbnail of Metal Substitution in the Active Site of Nitrogenase MFe 7 S 9 (M = Mo 4+ , V 3+ , Fe 3+ )

Inorganic Chemistry, 2002

The unifying view that molybdenum is the essential component in nitrogenase has changed over the ... more The unifying view that molybdenum is the essential component in nitrogenase has changed over the past few years with the discovery of a vanadium-containing nitrogenase and an iron-only nitrogenase. The principal question that has arisen for the alternative nitrogenases concerns the structures of their corresponding cofactors and their metal-ion valence assignments and whether there are significant differences with that of the more widely known molybdenum-iron cofactor (FeMoco). Spin-polarized broken-symmetry (BS) density functional theory (DFT) calculations are used to assess which of the two possible metal-ion valence assignments (4Fe(2+)4Fe(3+) or 6Fe(2+)2Fe(3+)) for the iron-only cofactor (FeFeco) best represents the resting state. For the 6Fe(2+)2Fe(3+) oxidation state, the spin coupling pattern for several spin state alignments compatible with S = 0 were generated and assessed by energy criteria. The most likely BS spin state is composed of a 4Fe cluster with spin S(a) = (7)/(2) antiferromagnetically coupled to a 4Fe' cluster with spin S(b) = (7)/(2). This state has the lowest DFT energy for the isolated FeFeco cluster and displays calculated Mössbauer isomer shifts consistent with experiment. Although the S = 0 resting state of FeFeco has recently been proposed to have metal-ion valencies of 4Fe(2+)4Fe(3+) (derived from experimental Mössbauer isomer shifts), our isomer shift calculations for the 4Fe(2+)4Fe(3+) oxidation state are in poorer agreement with experiment. Using the Mo(4+)6Fe(2+)Fe(3+) oxidation level of the cofactor as a starting point, the structural consequences of replacement of molybdenum (Mo(4+)) with vanadium (V(3+)) or iron (Fe(3+)) in the cofactor have been investigated. The size of the cofactor cluster shows a dependency on the nature of the heterometal and increases in the order FeMoco < FeVco < FeFeco.

Research paper thumbnail of BindingDB in 2015: A public database for medicinal chemistry, computational chemistry and systems pharmacology

Nucleic acids research, Jan 19, 2015

BindingDB, www.bindingdb.org, is a publicly accessible database of experimental protein-small mol... more BindingDB, www.bindingdb.org, is a publicly accessible database of experimental protein-small molecule interaction data. Its collection of over a million data entries derives primarily from scientific articles and, increasingly, US patents. BindingDB provides many ways to browse and search for data of interest, including an advanced search tool, which can cross searches of multiple query types, including text, chemical structure, protein sequence and numerical affinities. The PDB and PubMed provide links to data in BindingDB, and vice versa; and BindingDB provides links to pathway information, the ZINC catalog of available compounds, and other resources. The BindingDB website offers specialized tools that take advantage of its large data collection, including ones to generate hypotheses for the protein targets bound by a bioactive compound, and for the compounds bound by a new protein of known sequence; and virtual compound screening by maximal chemical similarity, binary kernel dis...

Research paper thumbnail of Cover Picture

Research paper thumbnail of Use of Broken-Symmetry Density Functional Theory To Characterize the IspH Oxidized State: Implications for IspH Mechanism and Inhibition

Journal of Chemical Theory and Computation, 2014

With current therapies becoming less efficacious due to increased drug resistance, new inhibitors... more With current therapies becoming less efficacious due to increased drug resistance, new inhibitors of both bacterial and malarial targets are desperately needed. The recently discovered methylerythritol phosphate (MEP) pathway for isoprenoid synthesis provides novel targets for the development of such drugs. Particular attention has focused on the IspH protein, the final enzyme in the MEP pathway, which uses its [4Fe-4S] cluster to catalyze the formation of the isoprenoid precursors IPP and DMAPP from HMBPP. IspH catalysis is achieved via a 2e (-)/2H(+) reductive dehydroxylation of HMBPP; the mechanism by which catalysis is achieved, however, is highly controversial. The work presented herein provides the first step in assessing different routes to catalysis by using computational methods. By performing broken-symmetry density functional theory (BS-DFT) calculations that employ both the conductor-like screening solvation model (DFT/COSMO) and a finite-difference Poisson-Boltzmann self-consistent reaction field methodology (DFT/SCRF), we evaluate geometries, energies, and Mössbauer signatures of the different protonation states that may exist in the oxidized state of the IspH catalytic cycle. From DFT/SCRF computations performed on the oxidized state, we find a state where the substrate, HMBPP, coordinates the apical iron in the [4Fe-4S] cluster as an alcohol group (ROH) to be one of two, isoenergetic, lowest-energy states. In this state, the HMBPP pyrophosphate moiety and an adjacent glutamate residue (E126) are both fully deprotonated, making the active site highly anionic. Our findings that this low-energy state also matches the experimental geometry of the active site and that its computed isomer shifts agree with experiment validate the use of the DFT/SCRF method to assess relative energies along the IspH reaction pathway. Additional studies of IspH catalytic intermediates are currently being pursued.

Research paper thumbnail of Quantitative Prediction of Fluorescence Quantum Yields for Tryptophan in Proteins

The Journal of Physical Chemistry B, 2004

Research paper thumbnail of BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities

Nucleic Acids Research, 2007

BindingDB (http://www.bindingdb.org) is a publicly accessible database currently containing 20 00... more BindingDB (http://www.bindingdb.org) is a publicly accessible database currently containing 20 000 experimentally determined binding affinities of protein-ligand complexes, for 110 protein targets including isoforms and mutational variants, and 11 000 small molecule ligands. The data are extracted from the scientific literature, data collection focusing on proteins that are drug-targets or candidate drug-targets and for which structural data are present in the Protein Data Bank. The BindingDB website supports a range of query types, including searches by chemical structure, substructure and similarity; protein sequence; ligand and protein names; affinity ranges and molecular weight. Data sets generated by BindingDB queries can be downloaded in the form of annotated SDfiles for further analysis, or used as the basis for virtual screening of a compound database uploaded by the user. The data in BindingDB are linked both to structural data in the PDB via PDB IDs and chemical and sequence searches, and to the literature in PubMed via PubMed IDs.

Research paper thumbnail of Characterization of the PEO-PPO-PEO Triblock Copolymer and Its Application as a Separation Medium in Capillary Electrophoresis

Macromolecules, 1997

... The cmc value was estimated by the intersection of the two linear regression lines with cmc =... more ... The cmc value was estimated by the intersection of the two linear regression lines with cmc = 6.1 mg/mL for F127 in 1X TBE buffer at 25 °C. The relative excess scattered intensity I ex was calculated by (I − I 0 )/I BZ , where I, I 0 , and I BZ are the scattered intensity of polymer ...

Research paper thumbnail of FeMo Cofactor of Nitrogenase:  A Density Functional Study of States M N , M OX , M R , and M I

Journal of the American Chemical Society, 2001

The M(N) S = (3)/(2) resting state of the FeMo cofactor of nitrogenase has been proposed to have ... more The M(N) S = (3)/(2) resting state of the FeMo cofactor of nitrogenase has been proposed to have metal-ion valencies of either Mo(4+)6Fe(2+)Fe(3+) (derived from metal hyperfine interactions) or Mo(4+)4Fe(2+)3Fe(3+) (from Mössbauer isomer shifts). Spin-polarized broken-symmetry (BS) density functional theory (DFT) calculations have been undertaken to determine which oxidation level best represents the M(N) state and to provide a framework for understanding its energetics and spectroscopy. For the Mo(4+)6Fe(2+)Fe(3+) oxidation state, the spin coupling pattern for several spin state alignments compatible with S = (3)/(2) were generated and assessed by energy and geometric criteria. The most likely BS spin state is composed of a Mo3Fe cluster with spin S(a) = 2 antiferromagnetically coupled to a 4Fe' cluster with spin S(b) = (7)/(2). This state has a low DFT energy for the isolated FeMoco cluster and the lowest energy when the interaction with the protein and solvent environment is included. This spin state also displays calculated metal hyperfine and Mössbauer isomer shifts compatible with experiment, and optimized geometries that are in excellent agreement with the protein X-ray data. Our best model for the actual spin-coupled state within FeMoco alters this BS state by a slight canting of spins and is analogous in several respects to that found in the 8Fe P-cluster in the same protein. The spin-up and spin-down components of the LUMO contain atomic contributions from Mo(4+) and the homocitrate and from the central prismane Fe sites and muS(2) atoms, respectively. This qualitative picture of the accepting orbitals for M(N) is consistent with observations from Mössbauer spectra of the one-electron reduced states. Similar calculations for the Mo(4+)4Fe(2+)3Fe(3+) oxidation state yield results that are in poorer agreement with experiment. Using the Mo(4+)6Fe(2+)Fe(3+) oxidation level as the most plausible resting state, the geometric, electronic and energetic properties of the one-electron redox transition to the oxidized state, M(OX), catalytically observed M(R) and radiolytically reduced M(I) states have also been explored.

Research paper thumbnail of Structural, Spectroscopic, and Redox Consequences of a Central Ligand in the FeMoco of Nitrogenase:  A Density Functional Theoretical Study

Journal of the American Chemical Society, 2003

Broken symmetry density functional and electrostatics calculations have been used to shed light o... more Broken symmetry density functional and electrostatics calculations have been used to shed light on which of three proposed atoms, C, N, or O, is most likely to be present in the center of the FeMoco, the active site of nitrogenase. At the Mo(4+)4Fe(2+)3Fe(3+) oxidation level, a central N(3-) anion results in (1) calculated Fe-N bond distances that are in very good agreement with the recent high-resolution X-ray data of Einsle et al.; (2) a calculated redox potential of 0.19 eV versus the standard hydrogen electrode (SHE) for FeMoco(oxidized) + e(-) --> FeMoco(resting), in good agreement with the measured value of -0.042 V in Azotobacter vinelandii; and (3) average Mössbauer isomer shift values (IS(av) = 0.48 mm s(-1)) compatible with experiment (IS(av) = 0.40 mm s(-1)). At the more reduced Mo(4+)6Fe(2+)1Fe(3+) level, the calculated geometry around a central N(3-) anion still correlates well with the X-ray data, but the average Mössbauer isomer shift value (IS(av) = 0.54 mm s(-1)) and the redox potential of -2.21 eV show a much poorer agreement with experiment. These calculated structural, spectroscopic, and redox data indicate the most likely iron oxidation state for the resting FeMoco of nitrogenase to be 4Fe(2+)3Fe(3+). At this favored oxidation state, oxygen or carbon coordination leads to (1) Fe-O distances in poor agreement and Fe-C distances in good agreement with experiment and (2) calculated redox potentials of +0.97 eV for O(2-) and -1.31 eV for C(4-). The calculated structural parameters and/or redox data suggest either O(2-) or C(4-) is unlikely as a central anion.

Research paper thumbnail of Ionization Potentials of Fluoroindoles and the Origin of Nonexponential Tryptophan Fluorescence Decay in Proteins ⊥

Journal of the American Chemical Society, 2005

This work reports an explanation for the unusual monoexponential fluorescence decay of 5-fluorotr... more This work reports an explanation for the unusual monoexponential fluorescence decay of 5-fluorotryptophan (5FTrp) in single-Trp mutant proteins [Broos, J.; Maddalena, F.; Hesp, B. H. J. Am. Chem. Soc. 2004, 126,2 2 -23] and substantially clarifies the origin of the ubiquitous nonexponential fluorescence decay of tryptophan in proteins. Our results strongly suggest that the extent of nonexponential fluorescence decay is governed primarily by the efficiency of electron transfer (ET) quenching by a nearby amide group in the peptide bond. Fluoro substitution increases the ionization potential (IP) of indole, thereby suppressing the ET rate, leading to a longer average lifetime and therefore a more homogeneous decay. We report experimental IPs for a number of substituted indoles including 5-fluoroindole, 5-fluoro-3methylindole, and 6-fluoroindole, along with accurate ab initio calculations of the IPs for these and 20 related molecules. The results predict the IP of 5-fluorotryptophan to be 0.19 eV higher than that of tryptophan. 5-Fluoro substitution does not measurably alter the excitation-induced change in permanent dipole moment nor does it change the fluorescent state from 1 La to 1 Lb. In combination with electronic structure information this argues that the increased IP and the decreased excitation energy of the 1 La state, together 0.3 eV, are solely responsible for the strong reduction of electron transfer quenching. 6-Fluoro substitution is predicted to increase the IP by a mere 0.09 eV. In agreement with our conclusions, the fluorescence decay curves of 6-fluorotryptophan-containing proteins are well fit using only two decay times compared to three required for Trp.

Research paper thumbnail of Public Domain Databases for Medicinal Chemistry

Journal of Medicinal Chemistry, 2012

ABSTRACT Historically, medicinal chemistry data were not well connected to the informatics world,... more ABSTRACT Historically, medicinal chemistry data were not well connected to the informatics world, but this situation has now changed decisively. Here, we have focused on three prominent, publicly accessible chemical activity databases, BindingDB, ChEMBL, and PubChem, each with its own unique user interface and scientific focus. These resources allow users to browse, query, and download hundreds of thousands of data extracted from the medicinal chemistry literature, along with additional data from other sources, such as the NIH screening centers. We also more briefly reviewed seven complementary chemical databases also of interest to many medicinal chemists. Analyses of the holdings of BindingDB and ChEMBL indicate that the rate of publication of medicinal chemistry data has grown by about 50% since 2007 and appears to continue on an upward trend. This is exciting scientifically but also means the work of extracting and managing the data is growing. We therefore discussed potential approaches to strengthening the database system, including further coordination among the various projects, community quality control efforts, and the development of a simple mechanism for authors to make their data available in electronic format concurrently with publication. Finally, we discussed future research capabilities that will grow from integration of the medicinal chemistry databases with more biologically oriented databases, as well as with Web-based tools for computational analysis and prediction. In sum, the emerging system of publicly accessible medicinal chemistry databases is rapidly becoming a critical infrastructure component for drug discovery efforts worldwide and is opening doors to valuable, new applications at the interfaces of chemistry and biology.

Research paper thumbnail of Correlation between calculated fermi contact spin densities and experimental contact shifts of paramagnetic iron-porphyrins. A novel approach to the electronic structure of intermediate-spin iron(II) porphyrin

Journal of Inorganic Biochemistry, 2003

Research paper thumbnail of DFT calculations of57Fe Mössbauer isomer shifts and quadrupole splittings for iron complexes in polar dielectric media: Applications to methane monooxygenase and ribonucleotide reductase

Journal of Computational Chemistry, 2006

To predict the isomer shifts of Fe complexes in different oxidation and spin states more accurate... more To predict the isomer shifts of Fe complexes in different oxidation and spin states more accurately, we have performed linear regression between the measured isomer shifts (␦ exp ) and DFT (PW91 potential with all-electron triple-plus polarization basis sets) calculated electron densities at Fe nuclei [(0)] for the Fe 2ϩ,2.5ϩ and Fe 2.5ϩ,3ϩ,3.5ϩ,4ϩ complexes separately. The geometries and electronic structures of all complexes in the training sets are optimized within the conductor like screening (COSMO) solvation model. Based on the linear correlation equation ␦ exp ϭ ␣[(0) Ϫ 11884.0] ϩ C, the best fitting for 17 Fe 2ϩ,2.5ϩ complexes (totally 31 Fe sites) yields ␣ ϭ Ϫ0.405 Ϯ 0.042 and C ϭ 0.735 Ϯ 0.047 mm s Ϫ1 . The correlation coefficient is r ϭ Ϫ0.876 with a standard deviation of SD ϭ 0.075 mm s Ϫ1 . In contrast, the linear fitting for 19 Fe 2.5ϩ,3ϩ,3.5ϩ,4ϩ complexes (totally 30 Fe sites) yields ␣ ϭ Ϫ0.393 Ϯ 0.030 and C ϭ 0.435 Ϯ 0.014 mm s Ϫ1 , with the correlation coefficient r ϭ Ϫ0.929 and a standard deviation SD ϭ 0.077 mm s Ϫ1 . We provide a physical rationale for separating the Fe 2ϩ,2.5ϩ fit from the Fe 2.5ϩ,3ϩ,3.5ϩ,4ϩ fit, which also is clearly justified on a statistical empirical basis. Quadrupole splittings have also been calculated for these systems. The correlation between the calculated (⌬E Q(cal) ) and experimental (⌬E Q(exp) ) quadrupole splittings based on ͉⌬E Q(exp) ͉ ϭ A ͉⌬E Q(cal) ͉ ϩ B yields slope A, which is almost the ideal value 1.0 (A ϭ 1.002 Ϯ 0.030) and intercept B almost zero (B ϭ 0.033 Ϯ 0.068 mm s Ϫ1 ). Further calculations on the reduced diferrous and oxidized diferric active sites of class-I ribonucleotide reductase (RNR) and the hydroxylase component of methane monooxygenase (MMOH), and on a mixed-valent [(tpb)Fe 3ϩ (-O)(-CH 3 CO 2 )Fe 4ϩ (Me 3 [9]aneN 3 )] 2ϩ (S ϭ 3/2) complex and its corresponding diferric state have been performed. Calculated results are in very good agreement with the experimental data.

Research paper thumbnail of Structural model studies for the high-valent intermediate Q of methane monooxygenase from broken-symmetry density functional calculations

Inorganica Chimica Acta, 2008

Mössbauer isomer shift parameters have been obtained for both density functional theory (DFT) OPB... more Mössbauer isomer shift parameters have been obtained for both density functional theory (DFT) OPBE and OLYP functionals by linear regressions between the measured isomer shifts and calculated electron densities at Fe nuclei for a number of Fe 2+,2.5+ and Fe 2.5+,3+,3.5+,4+ complexes grouped separately. The calculated isomer shifts and quadrupole splittings on the sample Fe complexes from OPBE and OLYP functionals are similar to those of PW91 calculations (J. Comput. Chem. 27 (2006) 1292), however the fit parameters from the linear regressions differ between PW91 and OPBE, OLYP. Four models for the active site structure of the hydroxylase component of soluble methane monooxygenase (MMOH) have been studied, using three DFT functionals OPBE, OLYP, and PW91, incorporated with broken-symmetry methodology and the conductor-like screening (COSMO) solvation model. The calculated properties, including optimized geometries, electronic energies, pK a 's, Fe net spin populations, and Mössbauer isomer shifts and quadrupole splittings, have been reported and compared with available experimental values. The high-spin antiferromagnetically (AF) coupled Fe 4+ sites are correctly predicted by OPBE and OLYP methods for all active site models. PW91 potential overestimates the Fe-ligand covalencies for some of the models because of spin crossover. Our calculations and data analysis support the structure (our current model II shown in ) proposed by Friesner and Lippard's group (J. Am. Chem. Soc. 123 (2001) 3836−3837), which contains an Fe 4+ (μ-O) 2 Fe 4+ center, one axial water which also H-bonds to both side chains of Glu243 and Glu114, and one bidentate carboxylate group from the side chain of Glu144, which is likely to represent the active site of MMOH-Q. A new model structure (model IV shown in ), which has a terminal hydroxo and a protonated His147 which is dissociated from a nearby Fe, is more asymmetric in its Fe(μ-O) 2 Fe diamond core, and is another very good candidate for intermediate Q.

Research paper thumbnail of Metal Substitution in the Active Site of Nitrogenase MFe 7 S 9 (M = Mo 4+ , V 3+ , Fe 3+ )

Inorganic Chemistry, 2002

The unifying view that molybdenum is the essential component in nitrogenase has changed over the ... more The unifying view that molybdenum is the essential component in nitrogenase has changed over the past few years with the discovery of a vanadium-containing nitrogenase and an iron-only nitrogenase. The principal question that has arisen for the alternative nitrogenases concerns the structures of their corresponding cofactors and their metal-ion valence assignments and whether there are significant differences with that of the more widely known molybdenum-iron cofactor (FeMoco). Spin-polarized broken-symmetry (BS) density functional theory (DFT) calculations are used to assess which of the two possible metal-ion valence assignments (4Fe(2+)4Fe(3+) or 6Fe(2+)2Fe(3+)) for the iron-only cofactor (FeFeco) best represents the resting state. For the 6Fe(2+)2Fe(3+) oxidation state, the spin coupling pattern for several spin state alignments compatible with S = 0 were generated and assessed by energy criteria. The most likely BS spin state is composed of a 4Fe cluster with spin S(a) = (7)/(2) antiferromagnetically coupled to a 4Fe' cluster with spin S(b) = (7)/(2). This state has the lowest DFT energy for the isolated FeFeco cluster and displays calculated Mössbauer isomer shifts consistent with experiment. Although the S = 0 resting state of FeFeco has recently been proposed to have metal-ion valencies of 4Fe(2+)4Fe(3+) (derived from experimental Mössbauer isomer shifts), our isomer shift calculations for the 4Fe(2+)4Fe(3+) oxidation state are in poorer agreement with experiment. Using the Mo(4+)6Fe(2+)Fe(3+) oxidation level of the cofactor as a starting point, the structural consequences of replacement of molybdenum (Mo(4+)) with vanadium (V(3+)) or iron (Fe(3+)) in the cofactor have been investigated. The size of the cofactor cluster shows a dependency on the nature of the heterometal and increases in the order FeMoco < FeVco < FeFeco.

Research paper thumbnail of DFT Calculations of Isomer Shifts and Quadrupole Splitting Parameters in Synthetic Iron−Oxo Complexes:  Applications to Methane Monooxygenase and Ribonucleotide Reductase

Inorganic Chemistry, 2003

To predict isomer shifts and quadrupole splitting parameters of Fe atoms in the protein active si... more To predict isomer shifts and quadrupole splitting parameters of Fe atoms in the protein active sites of methane monooxygenase and ribonucleotide reductase, a correlation between experimental isomer shifts ranging 0.1-1.5 mm s(-)(1) for Fe atoms in a training set with the corresponding density functional theory (DFT) calculated electron densities at the Fe nuclei in those complexes is established. The geometries of the species in the training set, consisting of synthetic polar monomeric and dimeric iron complexes, are taken from the Cambridge structural database. A comparison of calculated Mössbauer parameters for Fe atoms from complexes in the training set with their corresponding experimental values shows very good agreement (standard deviation of 0.11 mm/s, correlation coefficient of -0.94). However, for the Fe atoms in the active sites of the structurally characterized proteins of methane monooxygenase and ribonucleotide reductase, the calculated Mössbauer parameters deviate more from their experimentally measured values. The high correlation that exists between calculated and observed quadrupole splitting and isomer shift parameters for the synthetic complexes leads us to conclude that the main source of the error arising for the protein active sites is due to the differing degrees of atomic-level resolution for the protein structural data, compared to the synthetic complexes in the training set. Much lower X-ray resolutions associated with the former introduce uncertainty in the accuracy of several bond lengths. This is ultimately reflected in the calculated isomer shifts and quadrupole splitting parameters of the Fe sites in the proteins. For the proteins, the closest correspondence between predicted and observed Mössbauer isomer shifts follows the order MMOH(red), RNR(red), MMOH(ox), and RNR(ox), with average deviations from experiment of 0.17, 0.17, 0.17-0.20, and 0.32 mm/s, but this requires DFT geometry optimization of the iron-oxo dimer complexes.

Research paper thumbnail of Insights into properties and energetics of iron–sulfur proteins from simple clusters to nitrogenase

Current Opinion in Chemical Biology, 2002

AF antiferromagnetic BS broken symmetry DFT density functional theory ENDOR electron-nuclear doub... more AF antiferromagnetic BS broken symmetry DFT density functional theory ENDOR electron-nuclear double resonance Fd ferredoxin HIPIP high-potential iron-sulfur protein HS high-spin LUMO lowest unoccupied molecular orbital PDR phthalate dioxygenase reductase RPBE revised Perdew-Burke-Enzerhoff SCF self-consistent-field Uncoupled state Heisenberg Broken symmetry 9J J (25/2)J (5/2)J Current Opinion in Chemical Biology

Research paper thumbnail of Density Functional Studies of the Ground- and Excited-State Potential-Energy Curves of Stilbenecis-trans Isomerization

ChemPhysChem, 2002

Using spin-unrestricted density functional theory (the VWN Becke-Perdew potential), including bro... more Using spin-unrestricted density functional theory (the VWN Becke-Perdew potential), including broken-symmetry and spin-projection methods, we have obtained the potential-energy curves as a function of the central torsional angle of stilbene in the ground (S0), the first excited triplet (T1), the first excited singlet (S1), and the doubly excited singlet (S2) states. The thermal trans-->cis isomerization of stilbene passes through a diradical broken-symmetry electronic structure around the twisted conformation (90 degrees central torsional angle) in the ground state. Our calculations support the proposed triplet mechanism for sensitized cis [symbol: see text] trans photoisomerization and the nonadiabatic singlet mechanism proposed by Orlandi and Siebrand. On the T1 potential-energy curve, the rotation of the C=C bond for both trans- and cis-stilbene will lead stilbene to the twisted conformation, from which the twisted stilbene will decay to the ground-state surface that is nearly isoenergetic with the T1 surface and has diradical electronic structure in the twisted region. On the S1 potential-energy curve, the energy increases in the direction from trans- to the twisted stilbene, and crosses with the neutral doubly excited S2 potential-energy curve, which has a minimum at the twisted structure and is lower in energy than the zwitterionic doubly excited state. The twisted stilbene around the energy minimum of the neutral doubly excited S2-state will decay onto the ground-state surface from where the rotation of the C=C bond leads the twisted stilbene to either the trans or cis configuration and the isomerization of stilbene is then completed. Similar studies have also been performed on a stilbene derivative with a substituent group, NHCOCH3.

Research paper thumbnail of A Theoretical Study of the UV/Visible Absorption and Emission Solvatochromic Properties of Solvent-Sensitive Dyes

ChemPhysChem, 2003

Using the density-functional vertical self-consistent reaction field (VSCRF) solvation model, inc... more Using the density-functional vertical self-consistent reaction field (VSCRF) solvation model, incorporated with the conductor-like screening model (COSMO) and the self-consistent reaction field (SCRF) methods, we have studied the solvatochromic shifts of both the absorption and emission bands of four solvent-sensitive dyes in different solutions. The dye molecules studied here are: S-TBA merocyanine, Abdel-Halim's merocyanine, the rigidified aminocoumarin C153, and Nile red. These dyes were selected because they exemplify different structural features likely to impact the solvent-sensitive fluorescence of ™push-pull∫, or merocyanine, fluorophores. All trends of the blue or red shifts were correctly predicted, comparing with the experimental observations. Explicit H-bonding interactions were also considered in several protic solutions like H 2 O, methanol and ethanol, showing that including explicit H-bonding solvent molecule(s) in the calculations is important to obtain the correct order of the excitation and emission energies. The geometries, electronic structures, dipole moments, and intra-and intermolecular charge transfers of the dyes in different solvents are also discussed.

Research paper thumbnail of Short range photoinduced electron transfer in proteins: QM-MM simulations of tryptophan and flavin fluorescence quenching in proteins

Chemical Physics, 2006

... In this paper we report the results of QM-MM simulations of the relative magnitude, fluctuati... more ... In this paper we report the results of QM-MM simulations of the relative magnitude, fluctuations, and relaxation of the energy difference between the flavin fluorescing state (S 1 ) and the lowest Tyr–flavin charge transfer (CT) state for two proteins, flavin reductase (Fre) [29] and ...

Research paper thumbnail of Metal Substitution in the Active Site of Nitrogenase MFe 7 S 9 (M = Mo 4+ , V 3+ , Fe 3+ )

Inorganic Chemistry, 2002

The unifying view that molybdenum is the essential component in nitrogenase has changed over the ... more The unifying view that molybdenum is the essential component in nitrogenase has changed over the past few years with the discovery of a vanadium-containing nitrogenase and an iron-only nitrogenase. The principal question that has arisen for the alternative nitrogenases concerns the structures of their corresponding cofactors and their metal-ion valence assignments and whether there are significant differences with that of the more widely known molybdenum-iron cofactor (FeMoco). Spin-polarized broken-symmetry (BS) density functional theory (DFT) calculations are used to assess which of the two possible metal-ion valence assignments (4Fe(2+)4Fe(3+) or 6Fe(2+)2Fe(3+)) for the iron-only cofactor (FeFeco) best represents the resting state. For the 6Fe(2+)2Fe(3+) oxidation state, the spin coupling pattern for several spin state alignments compatible with S = 0 were generated and assessed by energy criteria. The most likely BS spin state is composed of a 4Fe cluster with spin S(a) = (7)/(2) antiferromagnetically coupled to a 4Fe' cluster with spin S(b) = (7)/(2). This state has the lowest DFT energy for the isolated FeFeco cluster and displays calculated Mössbauer isomer shifts consistent with experiment. Although the S = 0 resting state of FeFeco has recently been proposed to have metal-ion valencies of 4Fe(2+)4Fe(3+) (derived from experimental Mössbauer isomer shifts), our isomer shift calculations for the 4Fe(2+)4Fe(3+) oxidation state are in poorer agreement with experiment. Using the Mo(4+)6Fe(2+)Fe(3+) oxidation level of the cofactor as a starting point, the structural consequences of replacement of molybdenum (Mo(4+)) with vanadium (V(3+)) or iron (Fe(3+)) in the cofactor have been investigated. The size of the cofactor cluster shows a dependency on the nature of the heterometal and increases in the order FeMoco < FeVco < FeFeco.

Research paper thumbnail of BindingDB in 2015: A public database for medicinal chemistry, computational chemistry and systems pharmacology

Nucleic acids research, Jan 19, 2015

BindingDB, www.bindingdb.org, is a publicly accessible database of experimental protein-small mol... more BindingDB, www.bindingdb.org, is a publicly accessible database of experimental protein-small molecule interaction data. Its collection of over a million data entries derives primarily from scientific articles and, increasingly, US patents. BindingDB provides many ways to browse and search for data of interest, including an advanced search tool, which can cross searches of multiple query types, including text, chemical structure, protein sequence and numerical affinities. The PDB and PubMed provide links to data in BindingDB, and vice versa; and BindingDB provides links to pathway information, the ZINC catalog of available compounds, and other resources. The BindingDB website offers specialized tools that take advantage of its large data collection, including ones to generate hypotheses for the protein targets bound by a bioactive compound, and for the compounds bound by a new protein of known sequence; and virtual compound screening by maximal chemical similarity, binary kernel dis...

Research paper thumbnail of Cover Picture

Research paper thumbnail of Use of Broken-Symmetry Density Functional Theory To Characterize the IspH Oxidized State: Implications for IspH Mechanism and Inhibition

Journal of Chemical Theory and Computation, 2014

With current therapies becoming less efficacious due to increased drug resistance, new inhibitors... more With current therapies becoming less efficacious due to increased drug resistance, new inhibitors of both bacterial and malarial targets are desperately needed. The recently discovered methylerythritol phosphate (MEP) pathway for isoprenoid synthesis provides novel targets for the development of such drugs. Particular attention has focused on the IspH protein, the final enzyme in the MEP pathway, which uses its [4Fe-4S] cluster to catalyze the formation of the isoprenoid precursors IPP and DMAPP from HMBPP. IspH catalysis is achieved via a 2e (-)/2H(+) reductive dehydroxylation of HMBPP; the mechanism by which catalysis is achieved, however, is highly controversial. The work presented herein provides the first step in assessing different routes to catalysis by using computational methods. By performing broken-symmetry density functional theory (BS-DFT) calculations that employ both the conductor-like screening solvation model (DFT/COSMO) and a finite-difference Poisson-Boltzmann self-consistent reaction field methodology (DFT/SCRF), we evaluate geometries, energies, and Mössbauer signatures of the different protonation states that may exist in the oxidized state of the IspH catalytic cycle. From DFT/SCRF computations performed on the oxidized state, we find a state where the substrate, HMBPP, coordinates the apical iron in the [4Fe-4S] cluster as an alcohol group (ROH) to be one of two, isoenergetic, lowest-energy states. In this state, the HMBPP pyrophosphate moiety and an adjacent glutamate residue (E126) are both fully deprotonated, making the active site highly anionic. Our findings that this low-energy state also matches the experimental geometry of the active site and that its computed isomer shifts agree with experiment validate the use of the DFT/SCRF method to assess relative energies along the IspH reaction pathway. Additional studies of IspH catalytic intermediates are currently being pursued.

Research paper thumbnail of Quantitative Prediction of Fluorescence Quantum Yields for Tryptophan in Proteins

The Journal of Physical Chemistry B, 2004

Research paper thumbnail of BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities

Nucleic Acids Research, 2007

BindingDB (http://www.bindingdb.org) is a publicly accessible database currently containing 20 00... more BindingDB (http://www.bindingdb.org) is a publicly accessible database currently containing 20 000 experimentally determined binding affinities of protein-ligand complexes, for 110 protein targets including isoforms and mutational variants, and 11 000 small molecule ligands. The data are extracted from the scientific literature, data collection focusing on proteins that are drug-targets or candidate drug-targets and for which structural data are present in the Protein Data Bank. The BindingDB website supports a range of query types, including searches by chemical structure, substructure and similarity; protein sequence; ligand and protein names; affinity ranges and molecular weight. Data sets generated by BindingDB queries can be downloaded in the form of annotated SDfiles for further analysis, or used as the basis for virtual screening of a compound database uploaded by the user. The data in BindingDB are linked both to structural data in the PDB via PDB IDs and chemical and sequence searches, and to the literature in PubMed via PubMed IDs.

Research paper thumbnail of Characterization of the PEO-PPO-PEO Triblock Copolymer and Its Application as a Separation Medium in Capillary Electrophoresis

Macromolecules, 1997

... The cmc value was estimated by the intersection of the two linear regression lines with cmc =... more ... The cmc value was estimated by the intersection of the two linear regression lines with cmc = 6.1 mg/mL for F127 in 1X TBE buffer at 25 °C. The relative excess scattered intensity I ex was calculated by (I − I 0 )/I BZ , where I, I 0 , and I BZ are the scattered intensity of polymer ...

Research paper thumbnail of FeMo Cofactor of Nitrogenase:  A Density Functional Study of States M N , M OX , M R , and M I

Journal of the American Chemical Society, 2001

The M(N) S = (3)/(2) resting state of the FeMo cofactor of nitrogenase has been proposed to have ... more The M(N) S = (3)/(2) resting state of the FeMo cofactor of nitrogenase has been proposed to have metal-ion valencies of either Mo(4+)6Fe(2+)Fe(3+) (derived from metal hyperfine interactions) or Mo(4+)4Fe(2+)3Fe(3+) (from Mössbauer isomer shifts). Spin-polarized broken-symmetry (BS) density functional theory (DFT) calculations have been undertaken to determine which oxidation level best represents the M(N) state and to provide a framework for understanding its energetics and spectroscopy. For the Mo(4+)6Fe(2+)Fe(3+) oxidation state, the spin coupling pattern for several spin state alignments compatible with S = (3)/(2) were generated and assessed by energy and geometric criteria. The most likely BS spin state is composed of a Mo3Fe cluster with spin S(a) = 2 antiferromagnetically coupled to a 4Fe' cluster with spin S(b) = (7)/(2). This state has a low DFT energy for the isolated FeMoco cluster and the lowest energy when the interaction with the protein and solvent environment is included. This spin state also displays calculated metal hyperfine and Mössbauer isomer shifts compatible with experiment, and optimized geometries that are in excellent agreement with the protein X-ray data. Our best model for the actual spin-coupled state within FeMoco alters this BS state by a slight canting of spins and is analogous in several respects to that found in the 8Fe P-cluster in the same protein. The spin-up and spin-down components of the LUMO contain atomic contributions from Mo(4+) and the homocitrate and from the central prismane Fe sites and muS(2) atoms, respectively. This qualitative picture of the accepting orbitals for M(N) is consistent with observations from Mössbauer spectra of the one-electron reduced states. Similar calculations for the Mo(4+)4Fe(2+)3Fe(3+) oxidation state yield results that are in poorer agreement with experiment. Using the Mo(4+)6Fe(2+)Fe(3+) oxidation level as the most plausible resting state, the geometric, electronic and energetic properties of the one-electron redox transition to the oxidized state, M(OX), catalytically observed M(R) and radiolytically reduced M(I) states have also been explored.

Research paper thumbnail of Structural, Spectroscopic, and Redox Consequences of a Central Ligand in the FeMoco of Nitrogenase:  A Density Functional Theoretical Study

Journal of the American Chemical Society, 2003

Broken symmetry density functional and electrostatics calculations have been used to shed light o... more Broken symmetry density functional and electrostatics calculations have been used to shed light on which of three proposed atoms, C, N, or O, is most likely to be present in the center of the FeMoco, the active site of nitrogenase. At the Mo(4+)4Fe(2+)3Fe(3+) oxidation level, a central N(3-) anion results in (1) calculated Fe-N bond distances that are in very good agreement with the recent high-resolution X-ray data of Einsle et al.; (2) a calculated redox potential of 0.19 eV versus the standard hydrogen electrode (SHE) for FeMoco(oxidized) + e(-) --> FeMoco(resting), in good agreement with the measured value of -0.042 V in Azotobacter vinelandii; and (3) average Mössbauer isomer shift values (IS(av) = 0.48 mm s(-1)) compatible with experiment (IS(av) = 0.40 mm s(-1)). At the more reduced Mo(4+)6Fe(2+)1Fe(3+) level, the calculated geometry around a central N(3-) anion still correlates well with the X-ray data, but the average Mössbauer isomer shift value (IS(av) = 0.54 mm s(-1)) and the redox potential of -2.21 eV show a much poorer agreement with experiment. These calculated structural, spectroscopic, and redox data indicate the most likely iron oxidation state for the resting FeMoco of nitrogenase to be 4Fe(2+)3Fe(3+). At this favored oxidation state, oxygen or carbon coordination leads to (1) Fe-O distances in poor agreement and Fe-C distances in good agreement with experiment and (2) calculated redox potentials of +0.97 eV for O(2-) and -1.31 eV for C(4-). The calculated structural parameters and/or redox data suggest either O(2-) or C(4-) is unlikely as a central anion.

Research paper thumbnail of Ionization Potentials of Fluoroindoles and the Origin of Nonexponential Tryptophan Fluorescence Decay in Proteins ⊥

Journal of the American Chemical Society, 2005

This work reports an explanation for the unusual monoexponential fluorescence decay of 5-fluorotr... more This work reports an explanation for the unusual monoexponential fluorescence decay of 5-fluorotryptophan (5FTrp) in single-Trp mutant proteins [Broos, J.; Maddalena, F.; Hesp, B. H. J. Am. Chem. Soc. 2004, 126,2 2 -23] and substantially clarifies the origin of the ubiquitous nonexponential fluorescence decay of tryptophan in proteins. Our results strongly suggest that the extent of nonexponential fluorescence decay is governed primarily by the efficiency of electron transfer (ET) quenching by a nearby amide group in the peptide bond. Fluoro substitution increases the ionization potential (IP) of indole, thereby suppressing the ET rate, leading to a longer average lifetime and therefore a more homogeneous decay. We report experimental IPs for a number of substituted indoles including 5-fluoroindole, 5-fluoro-3methylindole, and 6-fluoroindole, along with accurate ab initio calculations of the IPs for these and 20 related molecules. The results predict the IP of 5-fluorotryptophan to be 0.19 eV higher than that of tryptophan. 5-Fluoro substitution does not measurably alter the excitation-induced change in permanent dipole moment nor does it change the fluorescent state from 1 La to 1 Lb. In combination with electronic structure information this argues that the increased IP and the decreased excitation energy of the 1 La state, together 0.3 eV, are solely responsible for the strong reduction of electron transfer quenching. 6-Fluoro substitution is predicted to increase the IP by a mere 0.09 eV. In agreement with our conclusions, the fluorescence decay curves of 6-fluorotryptophan-containing proteins are well fit using only two decay times compared to three required for Trp.

Research paper thumbnail of Public Domain Databases for Medicinal Chemistry

Journal of Medicinal Chemistry, 2012

ABSTRACT Historically, medicinal chemistry data were not well connected to the informatics world,... more ABSTRACT Historically, medicinal chemistry data were not well connected to the informatics world, but this situation has now changed decisively. Here, we have focused on three prominent, publicly accessible chemical activity databases, BindingDB, ChEMBL, and PubChem, each with its own unique user interface and scientific focus. These resources allow users to browse, query, and download hundreds of thousands of data extracted from the medicinal chemistry literature, along with additional data from other sources, such as the NIH screening centers. We also more briefly reviewed seven complementary chemical databases also of interest to many medicinal chemists. Analyses of the holdings of BindingDB and ChEMBL indicate that the rate of publication of medicinal chemistry data has grown by about 50% since 2007 and appears to continue on an upward trend. This is exciting scientifically but also means the work of extracting and managing the data is growing. We therefore discussed potential approaches to strengthening the database system, including further coordination among the various projects, community quality control efforts, and the development of a simple mechanism for authors to make their data available in electronic format concurrently with publication. Finally, we discussed future research capabilities that will grow from integration of the medicinal chemistry databases with more biologically oriented databases, as well as with Web-based tools for computational analysis and prediction. In sum, the emerging system of publicly accessible medicinal chemistry databases is rapidly becoming a critical infrastructure component for drug discovery efforts worldwide and is opening doors to valuable, new applications at the interfaces of chemistry and biology.

Research paper thumbnail of Correlation between calculated fermi contact spin densities and experimental contact shifts of paramagnetic iron-porphyrins. A novel approach to the electronic structure of intermediate-spin iron(II) porphyrin

Journal of Inorganic Biochemistry, 2003

Research paper thumbnail of DFT calculations of57Fe Mössbauer isomer shifts and quadrupole splittings for iron complexes in polar dielectric media: Applications to methane monooxygenase and ribonucleotide reductase

Journal of Computational Chemistry, 2006

To predict the isomer shifts of Fe complexes in different oxidation and spin states more accurate... more To predict the isomer shifts of Fe complexes in different oxidation and spin states more accurately, we have performed linear regression between the measured isomer shifts (␦ exp ) and DFT (PW91 potential with all-electron triple-plus polarization basis sets) calculated electron densities at Fe nuclei [(0)] for the Fe 2ϩ,2.5ϩ and Fe 2.5ϩ,3ϩ,3.5ϩ,4ϩ complexes separately. The geometries and electronic structures of all complexes in the training sets are optimized within the conductor like screening (COSMO) solvation model. Based on the linear correlation equation ␦ exp ϭ ␣[(0) Ϫ 11884.0] ϩ C, the best fitting for 17 Fe 2ϩ,2.5ϩ complexes (totally 31 Fe sites) yields ␣ ϭ Ϫ0.405 Ϯ 0.042 and C ϭ 0.735 Ϯ 0.047 mm s Ϫ1 . The correlation coefficient is r ϭ Ϫ0.876 with a standard deviation of SD ϭ 0.075 mm s Ϫ1 . In contrast, the linear fitting for 19 Fe 2.5ϩ,3ϩ,3.5ϩ,4ϩ complexes (totally 30 Fe sites) yields ␣ ϭ Ϫ0.393 Ϯ 0.030 and C ϭ 0.435 Ϯ 0.014 mm s Ϫ1 , with the correlation coefficient r ϭ Ϫ0.929 and a standard deviation SD ϭ 0.077 mm s Ϫ1 . We provide a physical rationale for separating the Fe 2ϩ,2.5ϩ fit from the Fe 2.5ϩ,3ϩ,3.5ϩ,4ϩ fit, which also is clearly justified on a statistical empirical basis. Quadrupole splittings have also been calculated for these systems. The correlation between the calculated (⌬E Q(cal) ) and experimental (⌬E Q(exp) ) quadrupole splittings based on ͉⌬E Q(exp) ͉ ϭ A ͉⌬E Q(cal) ͉ ϩ B yields slope A, which is almost the ideal value 1.0 (A ϭ 1.002 Ϯ 0.030) and intercept B almost zero (B ϭ 0.033 Ϯ 0.068 mm s Ϫ1 ). Further calculations on the reduced diferrous and oxidized diferric active sites of class-I ribonucleotide reductase (RNR) and the hydroxylase component of methane monooxygenase (MMOH), and on a mixed-valent [(tpb)Fe 3ϩ (-O)(-CH 3 CO 2 )Fe 4ϩ (Me 3 [9]aneN 3 )] 2ϩ (S ϭ 3/2) complex and its corresponding diferric state have been performed. Calculated results are in very good agreement with the experimental data.

Research paper thumbnail of Structural model studies for the high-valent intermediate Q of methane monooxygenase from broken-symmetry density functional calculations

Inorganica Chimica Acta, 2008

Mössbauer isomer shift parameters have been obtained for both density functional theory (DFT) OPB... more Mössbauer isomer shift parameters have been obtained for both density functional theory (DFT) OPBE and OLYP functionals by linear regressions between the measured isomer shifts and calculated electron densities at Fe nuclei for a number of Fe 2+,2.5+ and Fe 2.5+,3+,3.5+,4+ complexes grouped separately. The calculated isomer shifts and quadrupole splittings on the sample Fe complexes from OPBE and OLYP functionals are similar to those of PW91 calculations (J. Comput. Chem. 27 (2006) 1292), however the fit parameters from the linear regressions differ between PW91 and OPBE, OLYP. Four models for the active site structure of the hydroxylase component of soluble methane monooxygenase (MMOH) have been studied, using three DFT functionals OPBE, OLYP, and PW91, incorporated with broken-symmetry methodology and the conductor-like screening (COSMO) solvation model. The calculated properties, including optimized geometries, electronic energies, pK a 's, Fe net spin populations, and Mössbauer isomer shifts and quadrupole splittings, have been reported and compared with available experimental values. The high-spin antiferromagnetically (AF) coupled Fe 4+ sites are correctly predicted by OPBE and OLYP methods for all active site models. PW91 potential overestimates the Fe-ligand covalencies for some of the models because of spin crossover. Our calculations and data analysis support the structure (our current model II shown in ) proposed by Friesner and Lippard's group (J. Am. Chem. Soc. 123 (2001) 3836−3837), which contains an Fe 4+ (μ-O) 2 Fe 4+ center, one axial water which also H-bonds to both side chains of Glu243 and Glu114, and one bidentate carboxylate group from the side chain of Glu144, which is likely to represent the active site of MMOH-Q. A new model structure (model IV shown in ), which has a terminal hydroxo and a protonated His147 which is dissociated from a nearby Fe, is more asymmetric in its Fe(μ-O) 2 Fe diamond core, and is another very good candidate for intermediate Q.

Research paper thumbnail of Metal Substitution in the Active Site of Nitrogenase MFe 7 S 9 (M = Mo 4+ , V 3+ , Fe 3+ )

Inorganic Chemistry, 2002

The unifying view that molybdenum is the essential component in nitrogenase has changed over the ... more The unifying view that molybdenum is the essential component in nitrogenase has changed over the past few years with the discovery of a vanadium-containing nitrogenase and an iron-only nitrogenase. The principal question that has arisen for the alternative nitrogenases concerns the structures of their corresponding cofactors and their metal-ion valence assignments and whether there are significant differences with that of the more widely known molybdenum-iron cofactor (FeMoco). Spin-polarized broken-symmetry (BS) density functional theory (DFT) calculations are used to assess which of the two possible metal-ion valence assignments (4Fe(2+)4Fe(3+) or 6Fe(2+)2Fe(3+)) for the iron-only cofactor (FeFeco) best represents the resting state. For the 6Fe(2+)2Fe(3+) oxidation state, the spin coupling pattern for several spin state alignments compatible with S = 0 were generated and assessed by energy criteria. The most likely BS spin state is composed of a 4Fe cluster with spin S(a) = (7)/(2) antiferromagnetically coupled to a 4Fe' cluster with spin S(b) = (7)/(2). This state has the lowest DFT energy for the isolated FeFeco cluster and displays calculated Mössbauer isomer shifts consistent with experiment. Although the S = 0 resting state of FeFeco has recently been proposed to have metal-ion valencies of 4Fe(2+)4Fe(3+) (derived from experimental Mössbauer isomer shifts), our isomer shift calculations for the 4Fe(2+)4Fe(3+) oxidation state are in poorer agreement with experiment. Using the Mo(4+)6Fe(2+)Fe(3+) oxidation level of the cofactor as a starting point, the structural consequences of replacement of molybdenum (Mo(4+)) with vanadium (V(3+)) or iron (Fe(3+)) in the cofactor have been investigated. The size of the cofactor cluster shows a dependency on the nature of the heterometal and increases in the order FeMoco < FeVco < FeFeco.

Research paper thumbnail of DFT Calculations of Isomer Shifts and Quadrupole Splitting Parameters in Synthetic Iron−Oxo Complexes:  Applications to Methane Monooxygenase and Ribonucleotide Reductase

Inorganic Chemistry, 2003

To predict isomer shifts and quadrupole splitting parameters of Fe atoms in the protein active si... more To predict isomer shifts and quadrupole splitting parameters of Fe atoms in the protein active sites of methane monooxygenase and ribonucleotide reductase, a correlation between experimental isomer shifts ranging 0.1-1.5 mm s(-)(1) for Fe atoms in a training set with the corresponding density functional theory (DFT) calculated electron densities at the Fe nuclei in those complexes is established. The geometries of the species in the training set, consisting of synthetic polar monomeric and dimeric iron complexes, are taken from the Cambridge structural database. A comparison of calculated Mössbauer parameters for Fe atoms from complexes in the training set with their corresponding experimental values shows very good agreement (standard deviation of 0.11 mm/s, correlation coefficient of -0.94). However, for the Fe atoms in the active sites of the structurally characterized proteins of methane monooxygenase and ribonucleotide reductase, the calculated Mössbauer parameters deviate more from their experimentally measured values. The high correlation that exists between calculated and observed quadrupole splitting and isomer shift parameters for the synthetic complexes leads us to conclude that the main source of the error arising for the protein active sites is due to the differing degrees of atomic-level resolution for the protein structural data, compared to the synthetic complexes in the training set. Much lower X-ray resolutions associated with the former introduce uncertainty in the accuracy of several bond lengths. This is ultimately reflected in the calculated isomer shifts and quadrupole splitting parameters of the Fe sites in the proteins. For the proteins, the closest correspondence between predicted and observed Mössbauer isomer shifts follows the order MMOH(red), RNR(red), MMOH(ox), and RNR(ox), with average deviations from experiment of 0.17, 0.17, 0.17-0.20, and 0.32 mm/s, but this requires DFT geometry optimization of the iron-oxo dimer complexes.

Research paper thumbnail of Insights into properties and energetics of iron–sulfur proteins from simple clusters to nitrogenase

Current Opinion in Chemical Biology, 2002

AF antiferromagnetic BS broken symmetry DFT density functional theory ENDOR electron-nuclear doub... more AF antiferromagnetic BS broken symmetry DFT density functional theory ENDOR electron-nuclear double resonance Fd ferredoxin HIPIP high-potential iron-sulfur protein HS high-spin LUMO lowest unoccupied molecular orbital PDR phthalate dioxygenase reductase RPBE revised Perdew-Burke-Enzerhoff SCF self-consistent-field Uncoupled state Heisenberg Broken symmetry 9J J (25/2)J (5/2)J Current Opinion in Chemical Biology

Research paper thumbnail of Density Functional Studies of the Ground- and Excited-State Potential-Energy Curves of Stilbenecis-trans Isomerization

ChemPhysChem, 2002

Using spin-unrestricted density functional theory (the VWN Becke-Perdew potential), including bro... more Using spin-unrestricted density functional theory (the VWN Becke-Perdew potential), including broken-symmetry and spin-projection methods, we have obtained the potential-energy curves as a function of the central torsional angle of stilbene in the ground (S0), the first excited triplet (T1), the first excited singlet (S1), and the doubly excited singlet (S2) states. The thermal trans-->cis isomerization of stilbene passes through a diradical broken-symmetry electronic structure around the twisted conformation (90 degrees central torsional angle) in the ground state. Our calculations support the proposed triplet mechanism for sensitized cis [symbol: see text] trans photoisomerization and the nonadiabatic singlet mechanism proposed by Orlandi and Siebrand. On the T1 potential-energy curve, the rotation of the C=C bond for both trans- and cis-stilbene will lead stilbene to the twisted conformation, from which the twisted stilbene will decay to the ground-state surface that is nearly isoenergetic with the T1 surface and has diradical electronic structure in the twisted region. On the S1 potential-energy curve, the energy increases in the direction from trans- to the twisted stilbene, and crosses with the neutral doubly excited S2 potential-energy curve, which has a minimum at the twisted structure and is lower in energy than the zwitterionic doubly excited state. The twisted stilbene around the energy minimum of the neutral doubly excited S2-state will decay onto the ground-state surface from where the rotation of the C=C bond leads the twisted stilbene to either the trans or cis configuration and the isomerization of stilbene is then completed. Similar studies have also been performed on a stilbene derivative with a substituent group, NHCOCH3.

Research paper thumbnail of A Theoretical Study of the UV/Visible Absorption and Emission Solvatochromic Properties of Solvent-Sensitive Dyes

ChemPhysChem, 2003

Using the density-functional vertical self-consistent reaction field (VSCRF) solvation model, inc... more Using the density-functional vertical self-consistent reaction field (VSCRF) solvation model, incorporated with the conductor-like screening model (COSMO) and the self-consistent reaction field (SCRF) methods, we have studied the solvatochromic shifts of both the absorption and emission bands of four solvent-sensitive dyes in different solutions. The dye molecules studied here are: S-TBA merocyanine, Abdel-Halim's merocyanine, the rigidified aminocoumarin C153, and Nile red. These dyes were selected because they exemplify different structural features likely to impact the solvent-sensitive fluorescence of ™push-pull∫, or merocyanine, fluorophores. All trends of the blue or red shifts were correctly predicted, comparing with the experimental observations. Explicit H-bonding interactions were also considered in several protic solutions like H 2 O, methanol and ethanol, showing that including explicit H-bonding solvent molecule(s) in the calculations is important to obtain the correct order of the excitation and emission energies. The geometries, electronic structures, dipole moments, and intra-and intermolecular charge transfers of the dyes in different solvents are also discussed.

Research paper thumbnail of Short range photoinduced electron transfer in proteins: QM-MM simulations of tryptophan and flavin fluorescence quenching in proteins

Chemical Physics, 2006

... In this paper we report the results of QM-MM simulations of the relative magnitude, fluctuati... more ... In this paper we report the results of QM-MM simulations of the relative magnitude, fluctuations, and relaxation of the energy difference between the flavin fluorescing state (S 1 ) and the lowest Tyr–flavin charge transfer (CT) state for two proteins, flavin reductase (Fre) [29] and ...