Julian Tirado-rives - Academia.edu (original) (raw)

Papers by Julian Tirado-rives

Proceedings of the National Academy of Sciences of the United States of America, May 3, 2005

An overview is provided on the development and status of potential energy functions that are used... more An overview is provided on the development and status of potential energy functions that are used in atomic-level statistical mechanics and molecular dynamics simulations of water and of organic and biomolecular systems. Some topics that are considered are the form of force fields, their parameterization and performance, simulations of organic liquids, computation of free energies of hydration, universal extension for organic molecules, and choice of atomic charges. The discussion of water models covers some history, performance issues, and special topics such as nuclear quantum effects.

Journal of Chemical Information and Modeling, Aug 10, 2023

Biochemistry, Apr 23, 1991

ABSTRACT Molecular dynamics simulations of the S-peptide analogue AETAAAKFLREHMDS have been condu... more ABSTRACT Molecular dynamics simulations of the S-peptide analogue AETAAAKFLREHMDS have been conducted in aqueous solution for 300 ps at 278 K and for 500 ps in two different runs at 358 K. The results show agreement with experimental observations in that at low temperature, 5-degrees-C, the helix is stable, while unfolding is observed at 85-degrees-C. In the low-temperature simulation a solvent-separated ion pair was formed between Glu-2 and Arg-10, and the side chain of His-12 reoriented toward the C-terminal end of the alpha-helix. Detailed analyses of the unfolding pathways at high temperature have also revealed that the formation or disappearance of main-chain helical hydrogen bonds occurs frequently through an alpha reversible 3(10) reversible no hydrogen bond sequence.

Organic preparations and procedures international, Jun 1, 1988

Biochemistry, Jun 1, 1997

ABSTRACT Molecular dynamics simulations of barnase have been conducted both in water and in 8 M u... more ABSTRACT Molecular dynamics simulations of barnase have been conducted both in water and in 8 M urea solution for 500 ps at 25 degrees C and for 2000 ps at 85 degrees C. The final structure of the aqueous simulation at room temperature matches closely the structure obtained by NMR and the experimentally observed protections from isotopic exchange. The comparison of the structures generated by the aqueous simulation at 85 degrees C reveals a trajectory composed of groups of geometrically related structures separated by narrow regions of rapid change in structure. The first of these regions displays changes in backbone rmsd to the crystal structure and solvent-accessible area suggestive of a transition state, while the properties observed during the final 300 ps of the simulation are consistent with a stable intermediate. These assignments were confirmed by calculation of the "progress along the reaction coordinate" phi-values using an empirical equation based on a linear response method. The pathway of unfolding defined in this fashion agrees well with the experimental results of site-directed mutagenesis in terms of secondary structure content of the transition state and the intermediate and reproduces the relative stability of the different elements of secondary structure. The results of the simulations in urea suggest a mechanism at the molecular level for its well-known enhancement of the denaturation of proteins. The analysis of radial distribution functions shows that the first solvation shell of the protein is enriched in urea relative to the bulk solvent. The displacement of water molecules allows greater exposure of hydrophobic side chains, as witnessed particularly in the analysis of solvent-accessible surface areas at the higher temperature. Almost all urea molecules in the first shell form at least one hydrogen bond with the protein. They provide a more favorable environment for accommodation of the remaining water molecules, and they facilitate the separation of secondary structure elements by acting as a bridge between groups previously forming intraprotein hydrogen bonds.

Biochemistry, Apr 27, 1993

... The coordinates of the heme, the iron atom, crystallographic waters, and a phosphate were del... more ... The coordinates of the heme, the iron atom, crystallographic waters, and a phosphate were deleted, and two different protonation states of apomyoglobin were generated, depending on the pH. Although the precise Biochemistry, Vol. 32, No. 16, 1993 4177 . . . . . 1 >u I75 H ...

Journal of the American Chemical Society, Dec 1, 1993

Molecular dynamics and Monte Carlo simulations of a capped undecaalanine peptide were conducted t... more Molecular dynamics and Monte Carlo simulations of a capped undecaalanine peptide were conducted to determine the preferred helical conformation in water. The results clearly favor the a-helical form over the 310 alternative, in contrast to recent ESR findings. A molecular dynamics simulation started at the 310 conformation converges rapidly to an a-helix, and the free energy profile calculated via Monte Carlo simulations shows the a-helix to be more stable by ca. 1.0 kcalmmol-I per residue.

Journal of Physical Chemistry B, Aug 1, 2022

Torsion and Lennard-Jones parameters of the OPLS all-atom force field have been refined for descr... more Torsion and Lennard-Jones parameters of the OPLS all-atom force field have been refined for describing thermodynamics and dynamics of a wide range of liquid alkanes. Monte Carlo statistical mechanics (MC) and Molecular Dynamics (MD) simulations were carried out. For thermodynamics properties, MC simulations with truncated electrostatic interactions performed very closely to MD simulations with a Verlet neighbor list and the Particle Mesh Ewald algorithm. The average errors in comparison with experimental data for computed properties were improved with the modified force field (OPLS/2020), especially for long-chain alkanes. For liquid densities, heats of vaporization, and free energies of hydration, the average errors are 0.01 g/cm3, 0.2 kcal/mol, and ca. 0.5 kcal/mol, respectively; significant gains were made for relative heats of vaporization of isomeric series. Results for self-diffusion coefficients also reproduce well experimental data for linear alkane liquids up to hexadecane. The new force field is suitable for use in improved modeling of myriad systems of importance in chemistry, biology, and materials science.

European journal of medicinal chemistry, Dec 1, 2019

Cryptosporidiosis is a human gastrointestinal disease caused by protozoans of the genus Cryptospo... more Cryptosporidiosis is a human gastrointestinal disease caused by protozoans of the genus Cryptosporidium, which can be fatal in immunocompromised individuals. The essential enzyme, thymidylate synthase (TS), is responsible for de novo synthesis of deoxythymidine monophosphate. The TS active site is relatively conserved between Cryptosporidium and human enzymes. In previous work, we identified compound 1, (2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidin-methyl-phenyl-L-glutamic acid), as a promising selective Cryptosporidium hominis TS (ChTS) inhibitor. In the present study, we explore the structure-activity relationship around 1 glutamate moiety by synthesizing and biochemically evaluating the inhibitory activity of analogues against ChTS and human TS (hTS). X-Ray crystal structures were obtained for compounds bound to both ChTS and hTS. We establish the importance of the 2-phenylacetic acid moiety methylene linker in optimally positioning compounds 23, 24, and 25 within the active site. Moreover, through the comparison of structural data for 5, 14, 15, and 23 bound in both ChTS and hTS identified that active site rigidity is a driving force in determining inhibitor selectivity.

ACS Medicinal Chemistry Letters, 2021

Non-covalent inhibitors of the main protease (M pro) of SARS-CoV-2 having a pyridinone core were ... more Non-covalent inhibitors of the main protease (M pro) of SARS-CoV-2 having a pyridinone core were previously reported with IC 50 values as low as 0.018 μM for inhibition of enzymatic activity and EC 50 values as low as 0.8 μM for inhibition of viral replication in Vero E6 cells. The series has now been further advanced by consideration of placement of substituted five-membered-ring heterocycles in the S4 pocket of M pro and N-methylation of a uracil ring. Free energy perturbation calculations provided guidance on the choice of the heterocycles, and protein crystallography confirmed the desired S4 placement. Here we report inhibitors with EC 50 values as low as 0.080 μM, while remdesivir yields values of 0.5− 2 μM in side-by-side testing with infectious SARS-CoV-2. A key factor in the improvement is enhanced cell permeability, as reflected in PAMPA measurements. Compounds 19 and 21 are particularly promising as potential therapies for COVID-19, featuring IC 50 values of 0.044−0.061 μM, EC 50 values of ca. 0.1 μM, good aqueous solubility, and no cytotoxicity.

Acta Crystallographica Section C Crystal Structure Communications, 1985

The molecule has 1 symmetry in the crystal. The phenyl ring is twisted by 10.7 (3) ° out of the p... more The molecule has 1 symmetry in the crystal. The phenyl ring is twisted by 10.7 (3) ° out of the plane of the double bond. The olefinic C=C distance is unusually short, 1.284 (4) A.

The Journal of Physical Chemistry A, 2019

The prototypical S N 2 reaction of chloride ion with methyl chloride has been reinvestigated in a... more The prototypical S N 2 reaction of chloride ion with methyl chloride has been reinvestigated in aqueous solution using QM/MM methodology featuring MO6-2X/6-31+G(d) calculations with the TIP4P water model, and partial charges computed with the CM5 method. Though the DFT method yields excellent gas-phase energetics for the reaction, the QM/MM approach is found to yield overestimation of the activation barrier by ca. 12 kcal/mol. The discrepancy is traced to underestimate of the magnitude of the partial charges on the chlorine atoms in the transition structure. When CM1 or CM3 charges based on semiempirical wavefunctions are used instead, the agreement with experiment is much improved. The findings emphasize the sensitivity of the results of QM/MM calculations to the choice of QM method, the MM force field, and implementation of the QM/MM interface.

Journal of Chemical Theory and Computation, 2019

Accurate methods to estimate free energies play an important role for studying diverse condensedp... more Accurate methods to estimate free energies play an important role for studying diverse condensedphase problems in chemistry and biochemistry. The most common methods used in conjunction with molecular dynamics (MD) and Monte Carlo statistical mechanics (MC) simulations are free energy perturbation (FEP) and thermodynamic integration (TI). For common applications featuring the conversion of one molecule to another, simulations are run in stages or multiple "λwindows" to promote convergence of the results. For computation of absolute free energies of solvation or binding, calculations are needed in which the solute is typically annihilated in the solvent and in the complex. The present work addresses identification of optimal protocols for such calculations, specifically, the creation/annihilation of organic molecules in aqueous solution. As is common practice, decoupling of the perturbations for electrostatic and Lennard-Jones interactions was performed. Consistent with earlier reports, FEP calculations for molecular creations are much more efficient, while annihilations require many more windows and may converge to incorrect values. Strikingly, we find that as few as four windows may be adequate for creation calculations for solutes ranging from argon to ethylbenzene. For a larger drug-like molecule, MIF180, which contains 22 non-hydrogen atoms and three rotatable bonds, 10 creation windows are found to be adequate to yield the correct free energy of hydration. Convergence is impeded with procedures that use any sampling in the annihilation direction, and there is no need for post-processing methods such as BAR.

Journal of Chemical Theory and Computation, 2019

Significant improvements have been made to the OPLS-AA force field for modeling RNA. New torsiona... more Significant improvements have been made to the OPLS-AA force field for modeling RNA. New torsional potentials were optimized based on DFT scans at the ωB97X-D/6-311++G(d,p) level for potential energy surfaces of the backbone α and γ dihedral angles. In combination with previously reported improvements for the sugar puckering and glycosidic torsion terms, the new force field was validated through diverse molecular dynamics simulations for RNAs in aqueous solution. Results for dinucleotides and tetranucleotides revealed both accurate reproduction of 3 J couplings from NMR and the avoidance of several unphysical states observed with other force fields. Simulations of larger systems with noncanonical motifs showed significant structural improvements over the previous OPLS-AA parameters. The new force field, OPLSAA/M, is expected to perform competitively with other recent RNA force fields and to be compatible with OPLS-AA models for proteins and small molecules.

Journal of chemical theory and computation, Jan 12, 2018

The generation of a complete ensemble of geometrical configurations is required to obtain reliabl... more The generation of a complete ensemble of geometrical configurations is required to obtain reliable estimations of absolute binding free energies by alchemical free energy methods. Molecular dynamics (MD) is the most popular sampling method, but the representation of large biomolecular systems may be incomplete owing to energetic barriers that impede efficient sampling of the configurational space. Monte Carlo (MC) methods can possibly overcome this issue by adapting the attempted movement sizes to facilitate transitions between alternative local-energy minima. In this study, we present an MC statistical mechanics algorithm to explore the protein-ligand conformational space with emphasis on the motions of the protein backbone and side chains. The parameters for each MC move type were optimized to better reproduce conformational distributions of 18 dipeptides and the well-studied T4-lysozyme L99A protein. Next, the performance of the improved MC algorithms was evaluated by computing a...

Journal of Chemical Theory and Computation, 2015

The development and validation of new peptide dihedral parameters are reported for the OPLS-AA fo... more The development and validation of new peptide dihedral parameters are reported for the OPLS-AA force field. High accuracy quantum chemical methods were used to scan φ, ψ, χ 1 , and χ 2 potential energy surfaces for blocked dipeptides. New Fourier coefficients for the dihedral angle terms of the OPLS-AA force field were fit to these surfaces, utilizing a Boltzmann-weighted error function and systematically examining the effects of weighting temperature. To prevent overfitting to the available data, a minimal number of new residue-specific and peptide-specific torsion terms were developed. Extensive experimental solution-phase and quantum chemical gas-phase benchmarks were used to assess the quality of the new parameters, named OPLS-AA/M, demonstrating significant improvement over previous OPLS-AA force fields. A Boltzmann weighting temperature of 2000 K was determined to be optimal for fitting the new Fourier coefficients for dihedral angle parameters. Conclusions are drawn from the results for best practices for developing new torsion parameters for protein force fields.

The journal of physical chemistry. B, Jul 19, 2017

The atomic point-charge model used in most molecular mechanics force fields does not represent we... more The atomic point-charge model used in most molecular mechanics force fields does not represent well the electronic anisotropy that is featured in many directional non-covalent interactions. Sulfur participates in several types of such interactions with its lone pairs and σ-holes. The current study develops new models, via the addition of off-atom charged sites, for a variety of sulfur compounds in the OPLS-AA and OPLS/CM5 force fields to address the lack of charge anisotropy. Parameter optimization is carried out to reproduce liquid-state properties, torsional and non-covalent energetics from reliable quantum mechanical calculations, and electrostatic potentials. Significant improvements are obtained for computed free energies of hydration, reducing the mean unsigned errors from ca. 1.4 to 0.4-0.7 kcal/mol. Enhanced accuracy in directionality and energetics is also obtained for molecular complexes with sulfur-containing hydrogen and halogen bonds. Moreover, the new models reproduce ...

A consensus virtual screening protocol has been applied to ca. 2000 approved drugs to seek inhibi... more A consensus virtual screening protocol has been applied to ca. 2000 approved drugs to seek inhibitors of the main protease (M pro) of SARS-CoV-2, the virus responsible for COVID-19. 42 drugs emerged as top candidates, and after visual analyses of the predicted structures of their complexes with M pro , 17 were chosen for evaluation in a kinetic assay for M pro inhibition. Remarkably 14 of the compounds at 100-μM concentration were found to reduce the enzymatic activity and 5 provided IC 50 values below 40 μM: manidipine (4.8 μM), boceprevir (5.4 μM), lercanidipine (16.2 μM), bedaquiline (18.7 μM), and efonidipine (38.5 μM). Structural analyses reveal a common cloverleaf pattern for the binding of the active compounds to the P1, P1′, and P2 pockets of M pro. Further study of the most active compounds in the context of COVID-19 therapy is warranted, while all of the active compounds may provide a foundation for lead optimization to deliver valuable chemotherapeutics to combat the pandemic.

Bioorganic & Medicinal Chemistry Letters, 2013

Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved activity towards... more Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved activity towards Tyr181Cys containing variants was pursued with the assistance of free energy perturbation (FEP) calculations. Optimization of the 4-R substituent in 1 led to ethyl and isopropyl analogs 1e and 1f with 1-7 nM potency towards both the wild-type virus and a Tyr181C variant. Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are an important component of combination therapies for treatment of HIV infection. 1,2 Their further improvement is important to seek safer alternatives that can be given in low dosages and that may be needed to combat newly emerging viral variants. Compounds that can penetrate the blood-brain barrier well might provide an additional advance for addressing latent viral reservoirs. 3 A continuing challenge for developing NNRTIs is achievement of activity against clinically relevant viral variants that incorporate single and multiple mutations in the reverse transcriptase enzyme (HIV-RT). A particularly troublesome mutation has been Tyr181Cys (Y181C), which often arises quickly in patients who begin NNRTI therapy. 4 The first generation drugs, nevirapine and delavirdine, are inactive towards HIV-1 strains with this mutation, and the second-generation efavirenz is debilitated by Y181C when combined with Lys103Asn. 1,4 In contrast, the most recent introductions, etravirine and rilpivirine, show sub-10 nM potency in cell assays towards these variants and many others. 5

Proceedings of the National Academy of Sciences of the United States of America, May 3, 2005

An overview is provided on the development and status of potential energy functions that are used... more An overview is provided on the development and status of potential energy functions that are used in atomic-level statistical mechanics and molecular dynamics simulations of water and of organic and biomolecular systems. Some topics that are considered are the form of force fields, their parameterization and performance, simulations of organic liquids, computation of free energies of hydration, universal extension for organic molecules, and choice of atomic charges. The discussion of water models covers some history, performance issues, and special topics such as nuclear quantum effects.

Journal of Chemical Information and Modeling, Aug 10, 2023

Biochemistry, Apr 23, 1991

ABSTRACT Molecular dynamics simulations of the S-peptide analogue AETAAAKFLREHMDS have been condu... more ABSTRACT Molecular dynamics simulations of the S-peptide analogue AETAAAKFLREHMDS have been conducted in aqueous solution for 300 ps at 278 K and for 500 ps in two different runs at 358 K. The results show agreement with experimental observations in that at low temperature, 5-degrees-C, the helix is stable, while unfolding is observed at 85-degrees-C. In the low-temperature simulation a solvent-separated ion pair was formed between Glu-2 and Arg-10, and the side chain of His-12 reoriented toward the C-terminal end of the alpha-helix. Detailed analyses of the unfolding pathways at high temperature have also revealed that the formation or disappearance of main-chain helical hydrogen bonds occurs frequently through an alpha reversible 3(10) reversible no hydrogen bond sequence.

Organic preparations and procedures international, Jun 1, 1988

Biochemistry, Jun 1, 1997

ABSTRACT Molecular dynamics simulations of barnase have been conducted both in water and in 8 M u... more ABSTRACT Molecular dynamics simulations of barnase have been conducted both in water and in 8 M urea solution for 500 ps at 25 degrees C and for 2000 ps at 85 degrees C. The final structure of the aqueous simulation at room temperature matches closely the structure obtained by NMR and the experimentally observed protections from isotopic exchange. The comparison of the structures generated by the aqueous simulation at 85 degrees C reveals a trajectory composed of groups of geometrically related structures separated by narrow regions of rapid change in structure. The first of these regions displays changes in backbone rmsd to the crystal structure and solvent-accessible area suggestive of a transition state, while the properties observed during the final 300 ps of the simulation are consistent with a stable intermediate. These assignments were confirmed by calculation of the "progress along the reaction coordinate" phi-values using an empirical equation based on a linear response method. The pathway of unfolding defined in this fashion agrees well with the experimental results of site-directed mutagenesis in terms of secondary structure content of the transition state and the intermediate and reproduces the relative stability of the different elements of secondary structure. The results of the simulations in urea suggest a mechanism at the molecular level for its well-known enhancement of the denaturation of proteins. The analysis of radial distribution functions shows that the first solvation shell of the protein is enriched in urea relative to the bulk solvent. The displacement of water molecules allows greater exposure of hydrophobic side chains, as witnessed particularly in the analysis of solvent-accessible surface areas at the higher temperature. Almost all urea molecules in the first shell form at least one hydrogen bond with the protein. They provide a more favorable environment for accommodation of the remaining water molecules, and they facilitate the separation of secondary structure elements by acting as a bridge between groups previously forming intraprotein hydrogen bonds.

Biochemistry, Apr 27, 1993

... The coordinates of the heme, the iron atom, crystallographic waters, and a phosphate were del... more ... The coordinates of the heme, the iron atom, crystallographic waters, and a phosphate were deleted, and two different protonation states of apomyoglobin were generated, depending on the pH. Although the precise Biochemistry, Vol. 32, No. 16, 1993 4177 . . . . . 1 >u I75 H ...

Journal of the American Chemical Society, Dec 1, 1993

Molecular dynamics and Monte Carlo simulations of a capped undecaalanine peptide were conducted t... more Molecular dynamics and Monte Carlo simulations of a capped undecaalanine peptide were conducted to determine the preferred helical conformation in water. The results clearly favor the a-helical form over the 310 alternative, in contrast to recent ESR findings. A molecular dynamics simulation started at the 310 conformation converges rapidly to an a-helix, and the free energy profile calculated via Monte Carlo simulations shows the a-helix to be more stable by ca. 1.0 kcalmmol-I per residue.

Journal of Physical Chemistry B, Aug 1, 2022

Torsion and Lennard-Jones parameters of the OPLS all-atom force field have been refined for descr... more Torsion and Lennard-Jones parameters of the OPLS all-atom force field have been refined for describing thermodynamics and dynamics of a wide range of liquid alkanes. Monte Carlo statistical mechanics (MC) and Molecular Dynamics (MD) simulations were carried out. For thermodynamics properties, MC simulations with truncated electrostatic interactions performed very closely to MD simulations with a Verlet neighbor list and the Particle Mesh Ewald algorithm. The average errors in comparison with experimental data for computed properties were improved with the modified force field (OPLS/2020), especially for long-chain alkanes. For liquid densities, heats of vaporization, and free energies of hydration, the average errors are 0.01 g/cm3, 0.2 kcal/mol, and ca. 0.5 kcal/mol, respectively; significant gains were made for relative heats of vaporization of isomeric series. Results for self-diffusion coefficients also reproduce well experimental data for linear alkane liquids up to hexadecane. The new force field is suitable for use in improved modeling of myriad systems of importance in chemistry, biology, and materials science.

European journal of medicinal chemistry, Dec 1, 2019

Cryptosporidiosis is a human gastrointestinal disease caused by protozoans of the genus Cryptospo... more Cryptosporidiosis is a human gastrointestinal disease caused by protozoans of the genus Cryptosporidium, which can be fatal in immunocompromised individuals. The essential enzyme, thymidylate synthase (TS), is responsible for de novo synthesis of deoxythymidine monophosphate. The TS active site is relatively conserved between Cryptosporidium and human enzymes. In previous work, we identified compound 1, (2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidin-methyl-phenyl-L-glutamic acid), as a promising selective Cryptosporidium hominis TS (ChTS) inhibitor. In the present study, we explore the structure-activity relationship around 1 glutamate moiety by synthesizing and biochemically evaluating the inhibitory activity of analogues against ChTS and human TS (hTS). X-Ray crystal structures were obtained for compounds bound to both ChTS and hTS. We establish the importance of the 2-phenylacetic acid moiety methylene linker in optimally positioning compounds 23, 24, and 25 within the active site. Moreover, through the comparison of structural data for 5, 14, 15, and 23 bound in both ChTS and hTS identified that active site rigidity is a driving force in determining inhibitor selectivity.

ACS Medicinal Chemistry Letters, 2021

Non-covalent inhibitors of the main protease (M pro) of SARS-CoV-2 having a pyridinone core were ... more Non-covalent inhibitors of the main protease (M pro) of SARS-CoV-2 having a pyridinone core were previously reported with IC 50 values as low as 0.018 μM for inhibition of enzymatic activity and EC 50 values as low as 0.8 μM for inhibition of viral replication in Vero E6 cells. The series has now been further advanced by consideration of placement of substituted five-membered-ring heterocycles in the S4 pocket of M pro and N-methylation of a uracil ring. Free energy perturbation calculations provided guidance on the choice of the heterocycles, and protein crystallography confirmed the desired S4 placement. Here we report inhibitors with EC 50 values as low as 0.080 μM, while remdesivir yields values of 0.5− 2 μM in side-by-side testing with infectious SARS-CoV-2. A key factor in the improvement is enhanced cell permeability, as reflected in PAMPA measurements. Compounds 19 and 21 are particularly promising as potential therapies for COVID-19, featuring IC 50 values of 0.044−0.061 μM, EC 50 values of ca. 0.1 μM, good aqueous solubility, and no cytotoxicity.

Acta Crystallographica Section C Crystal Structure Communications, 1985

The molecule has 1 symmetry in the crystal. The phenyl ring is twisted by 10.7 (3) ° out of the p... more The molecule has 1 symmetry in the crystal. The phenyl ring is twisted by 10.7 (3) ° out of the plane of the double bond. The olefinic C=C distance is unusually short, 1.284 (4) A.

The Journal of Physical Chemistry A, 2019

The prototypical S N 2 reaction of chloride ion with methyl chloride has been reinvestigated in a... more The prototypical S N 2 reaction of chloride ion with methyl chloride has been reinvestigated in aqueous solution using QM/MM methodology featuring MO6-2X/6-31+G(d) calculations with the TIP4P water model, and partial charges computed with the CM5 method. Though the DFT method yields excellent gas-phase energetics for the reaction, the QM/MM approach is found to yield overestimation of the activation barrier by ca. 12 kcal/mol. The discrepancy is traced to underestimate of the magnitude of the partial charges on the chlorine atoms in the transition structure. When CM1 or CM3 charges based on semiempirical wavefunctions are used instead, the agreement with experiment is much improved. The findings emphasize the sensitivity of the results of QM/MM calculations to the choice of QM method, the MM force field, and implementation of the QM/MM interface.

Journal of Chemical Theory and Computation, 2019

Accurate methods to estimate free energies play an important role for studying diverse condensedp... more Accurate methods to estimate free energies play an important role for studying diverse condensedphase problems in chemistry and biochemistry. The most common methods used in conjunction with molecular dynamics (MD) and Monte Carlo statistical mechanics (MC) simulations are free energy perturbation (FEP) and thermodynamic integration (TI). For common applications featuring the conversion of one molecule to another, simulations are run in stages or multiple "λwindows" to promote convergence of the results. For computation of absolute free energies of solvation or binding, calculations are needed in which the solute is typically annihilated in the solvent and in the complex. The present work addresses identification of optimal protocols for such calculations, specifically, the creation/annihilation of organic molecules in aqueous solution. As is common practice, decoupling of the perturbations for electrostatic and Lennard-Jones interactions was performed. Consistent with earlier reports, FEP calculations for molecular creations are much more efficient, while annihilations require many more windows and may converge to incorrect values. Strikingly, we find that as few as four windows may be adequate for creation calculations for solutes ranging from argon to ethylbenzene. For a larger drug-like molecule, MIF180, which contains 22 non-hydrogen atoms and three rotatable bonds, 10 creation windows are found to be adequate to yield the correct free energy of hydration. Convergence is impeded with procedures that use any sampling in the annihilation direction, and there is no need for post-processing methods such as BAR.

Journal of Chemical Theory and Computation, 2019

Significant improvements have been made to the OPLS-AA force field for modeling RNA. New torsiona... more Significant improvements have been made to the OPLS-AA force field for modeling RNA. New torsional potentials were optimized based on DFT scans at the ωB97X-D/6-311++G(d,p) level for potential energy surfaces of the backbone α and γ dihedral angles. In combination with previously reported improvements for the sugar puckering and glycosidic torsion terms, the new force field was validated through diverse molecular dynamics simulations for RNAs in aqueous solution. Results for dinucleotides and tetranucleotides revealed both accurate reproduction of 3 J couplings from NMR and the avoidance of several unphysical states observed with other force fields. Simulations of larger systems with noncanonical motifs showed significant structural improvements over the previous OPLS-AA parameters. The new force field, OPLSAA/M, is expected to perform competitively with other recent RNA force fields and to be compatible with OPLS-AA models for proteins and small molecules.

Journal of chemical theory and computation, Jan 12, 2018

The generation of a complete ensemble of geometrical configurations is required to obtain reliabl... more The generation of a complete ensemble of geometrical configurations is required to obtain reliable estimations of absolute binding free energies by alchemical free energy methods. Molecular dynamics (MD) is the most popular sampling method, but the representation of large biomolecular systems may be incomplete owing to energetic barriers that impede efficient sampling of the configurational space. Monte Carlo (MC) methods can possibly overcome this issue by adapting the attempted movement sizes to facilitate transitions between alternative local-energy minima. In this study, we present an MC statistical mechanics algorithm to explore the protein-ligand conformational space with emphasis on the motions of the protein backbone and side chains. The parameters for each MC move type were optimized to better reproduce conformational distributions of 18 dipeptides and the well-studied T4-lysozyme L99A protein. Next, the performance of the improved MC algorithms was evaluated by computing a...

Journal of Chemical Theory and Computation, 2015

The development and validation of new peptide dihedral parameters are reported for the OPLS-AA fo... more The development and validation of new peptide dihedral parameters are reported for the OPLS-AA force field. High accuracy quantum chemical methods were used to scan φ, ψ, χ 1 , and χ 2 potential energy surfaces for blocked dipeptides. New Fourier coefficients for the dihedral angle terms of the OPLS-AA force field were fit to these surfaces, utilizing a Boltzmann-weighted error function and systematically examining the effects of weighting temperature. To prevent overfitting to the available data, a minimal number of new residue-specific and peptide-specific torsion terms were developed. Extensive experimental solution-phase and quantum chemical gas-phase benchmarks were used to assess the quality of the new parameters, named OPLS-AA/M, demonstrating significant improvement over previous OPLS-AA force fields. A Boltzmann weighting temperature of 2000 K was determined to be optimal for fitting the new Fourier coefficients for dihedral angle parameters. Conclusions are drawn from the results for best practices for developing new torsion parameters for protein force fields.

The journal of physical chemistry. B, Jul 19, 2017

The atomic point-charge model used in most molecular mechanics force fields does not represent we... more The atomic point-charge model used in most molecular mechanics force fields does not represent well the electronic anisotropy that is featured in many directional non-covalent interactions. Sulfur participates in several types of such interactions with its lone pairs and σ-holes. The current study develops new models, via the addition of off-atom charged sites, for a variety of sulfur compounds in the OPLS-AA and OPLS/CM5 force fields to address the lack of charge anisotropy. Parameter optimization is carried out to reproduce liquid-state properties, torsional and non-covalent energetics from reliable quantum mechanical calculations, and electrostatic potentials. Significant improvements are obtained for computed free energies of hydration, reducing the mean unsigned errors from ca. 1.4 to 0.4-0.7 kcal/mol. Enhanced accuracy in directionality and energetics is also obtained for molecular complexes with sulfur-containing hydrogen and halogen bonds. Moreover, the new models reproduce ...

A consensus virtual screening protocol has been applied to ca. 2000 approved drugs to seek inhibi... more A consensus virtual screening protocol has been applied to ca. 2000 approved drugs to seek inhibitors of the main protease (M pro) of SARS-CoV-2, the virus responsible for COVID-19. 42 drugs emerged as top candidates, and after visual analyses of the predicted structures of their complexes with M pro , 17 were chosen for evaluation in a kinetic assay for M pro inhibition. Remarkably 14 of the compounds at 100-μM concentration were found to reduce the enzymatic activity and 5 provided IC 50 values below 40 μM: manidipine (4.8 μM), boceprevir (5.4 μM), lercanidipine (16.2 μM), bedaquiline (18.7 μM), and efonidipine (38.5 μM). Structural analyses reveal a common cloverleaf pattern for the binding of the active compounds to the P1, P1′, and P2 pockets of M pro. Further study of the most active compounds in the context of COVID-19 therapy is warranted, while all of the active compounds may provide a foundation for lead optimization to deliver valuable chemotherapeutics to combat the pandemic.

Bioorganic & Medicinal Chemistry Letters, 2013

Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved activity towards... more Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved activity towards Tyr181Cys containing variants was pursued with the assistance of free energy perturbation (FEP) calculations. Optimization of the 4-R substituent in 1 led to ethyl and isopropyl analogs 1e and 1f with 1-7 nM potency towards both the wild-type virus and a Tyr181C variant. Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are an important component of combination therapies for treatment of HIV infection. 1,2 Their further improvement is important to seek safer alternatives that can be given in low dosages and that may be needed to combat newly emerging viral variants. Compounds that can penetrate the blood-brain barrier well might provide an additional advance for addressing latent viral reservoirs. 3 A continuing challenge for developing NNRTIs is achievement of activity against clinically relevant viral variants that incorporate single and multiple mutations in the reverse transcriptase enzyme (HIV-RT). A particularly troublesome mutation has been Tyr181Cys (Y181C), which often arises quickly in patients who begin NNRTI therapy. 4 The first generation drugs, nevirapine and delavirdine, are inactive towards HIV-1 strains with this mutation, and the second-generation efavirenz is debilitated by Y181C when combined with Lys103Asn. 1,4 In contrast, the most recent introductions, etravirine and rilpivirine, show sub-10 nM potency in cell assays towards these variants and many others. 5