Carsten Baldauf - Academia.edu (original) (raw)

Papers by Carsten Baldauf

Journal of Molecular Structure: THEOCHEM, 2004

A systematic analysis of the conformation of the sulfonamide bond at various levels of ab initio ... more A systematic analysis of the conformation of the sulfonamide bond at various levels of ab initio MO theory shows distinct differences in comparison to the amide/peptide bond. Most important are (i) the different values of the torsion angle v (/C a SNC a ), which are about 2 100 and 608 in the two basic conformers of the sulfonamide bond, but about 180 and 08 for the peptide bond, (ii) the rotation barriers around the SN bond, which are distinctly lower than for the peptide bond, thus making sulfonamido peptides more flexible, and (iii) the pyramidal nature of the sulfonamide nitrogen in the conformers in comparison to a practically planar arrangement of the peptide bond.

Proceedings of the 13th annual conference on Genetic and evolutionary computation - GECCO '11, 2011

The identification of protein binding sites and the prediction of protein-ligand complexes play a... more The identification of protein binding sites and the prediction of protein-ligand complexes play a key role in the pharmaceutical drug design process and many domains of life sciences. Computational approaches for protein-ligand docking (or molecular docking) have received increased attention over the last years as they allow inexpensive and fast prediction of protein-ligand complexes. Here we introduce the principle of Bee Nest-Site Selection Optimisation (BNSO), which solves optimisation problems using a novel scheme inspired by the nest-site selection behaviour found in honeybees. Moreover, the first BNSO algorithm -called Bee-Nest -is proposed and is applied to the protein-docking problem. The performance of Bee-Nest is tested on 173 docking instances from the PDBbind core set and compared to the performance of three reference algorithms. The results show that Bee-Nest could find ligand poses with very good energy levels. Interestingly, the reference Particle Swarm Optimization (PSO) produces results that are qualitatively closer to wet-lab experimentally derived complexes but of worse energy than Bee-Nest. Our results clearly highlight the superior performance of Bee-Nest in semi-local (regional) optimization for the molecular docking problem, and suggests its usefulness in a hybrid strategy.

The Journal of organic chemistry, Jan 3, 2006

Alpha,gamma- and beta,gamma-hybrid peptides, which are composed of two different homologous amino... more Alpha,gamma- and beta,gamma-hybrid peptides, which are composed of two different homologous amino acid constituents in alternate order, are suggested as novel classes of peptide foldamers. On the basis of a systematic conformational search employing the methods of ab initio MO theory, the possibilities for the formation of periodic secondary structures in these systems are described. The conformational analysis provides a great number of helix conformers widely differing in energy, which can be arranged into three groups: (i) helices with all hydrogen bonds formed in forward direction along the sequence, (ii) helices with all hydrogen bonds in backward direction, and (iii) helices with alternate hydrogen-bond directions (mixed or beta-helices). Most stable are representatives of beta-helices, but their stability decreases considerably in more polar environments in comparison to helix conformers from the other two classes. There is a great similarity between the overall topology of t...

The Journal of organic chemistry, Jan 8, 2005

A complete overview on the alternative and competitive helices in vinylogous γ-peptides is given,... more A complete overview on the alternative and competitive helices in vinylogous γ-peptides is given, which was obtained on the basis of a systematic conformational analysis at various levels of ab initio MO theory (HF/6-31G*, DFT/B3LYP/6-31G*, PCM/HF/6-31G*). Contrary to the parent γ-peptides, there is a strict control of helix formation by the configuration of the double bond between the C(R) and C( ) atoms of the monomer constituents. (E)-Double bonds favor helices with larger pseudocycles beginning with 14-up to 27-membered hydrogen-bonded rings, whereas the (Z)configuration of the double bonds supports a distinct preference of helices with smaller seven-and nine-membered pseudocycles showing interactions between nearest-neighbor peptide bonds. The rather stable helices of the (E)-vinylogous peptides with 22-, 24-, and 27-membered hydrogenbonded pseudocycles have inner diameters large enough to let molecules or ions pass. Thus, they could be interesting model compounds for the design of membrane channels and monomolecular nanotubes. Since (E)-and (Z)-vinylogous γ-amino acids and their oligomers are synthetically accessible, our study may stimulate structure research in this novel field of foldamers.

Biopolymers, 2005

A systematic analysis of the substituent influence on the formation of the unique secondary struc... more A systematic analysis of the substituent influence on the formation of the unique secondary structure type of "mixed" helices in the homologous alpha-, beta-, and gamma-peptides was performed on the basis of ab initio molecular orbital theory. Contrary to the common periodic peptide helices, mixed helices have an alternating periodicity and their hydrogen-bonding pattern is similar to those of beta-sheets. They belong, therefore, to the family of beta-helices. It is shown that folding of peptide sequences into mixed helices is energetically preferred over folding into their periodic counterparts in numerous cases. The influence of entropy and solvents on the formation of the various competitive mixed and periodic helix types is discussed. Among the oligomers of the various homologous amino acids, beta-peptides show the highest tendency to form beta-helices. The rules of substituent influence derived from the analysis of a wide variety of backbone substitution patterns migh...

The Journal of organic chemistry, Jan 17, 2004

An overview on all possible helix types in oligomers of delta-amino acids (delta-peptides) and th... more An overview on all possible helix types in oligomers of delta-amino acids (delta-peptides) and their stabilities is given on the basis of a systematic conformational analysis employing various methods of ab initio MO theory (HF/6-31G*, B3LYP/6-31G*, PCM//HF/6-31G*). A wide variety of novel helical structures with hydrogen-bonded pseudocycles of different size are predicted. Since a delta-amino acid constituent may replace a dipeptide unit in alpha-peptides, there are close relationships between the secondary structures of peptides with delta-amino acid residues and typical secondary structures of alpha-peptides. However, the preference of gauche conformations at the central C(beta)-C(gamma) bonds of delta-amino acids, which correspond to the peptide linkages in alpha-peptides, over staggered ones makes completely novel structure alternatives for helices and turns more probable. The peculiarities of beta-turn formation by sugar amino acids derived from delta-amino acids are compared ...

Physical chemistry chemical physics : PCCP, Jan 4, 2015

Reliable, quantitative predictions of the structure of peptides based on their amino-acid sequenc... more Reliable, quantitative predictions of the structure of peptides based on their amino-acid sequence information are an ongoing challenge. We here explore the energy landscapes of two unsolvated 20-residue peptides that result from a shift of the position of one amino acid in otherwise the same sequence. Our main goal is to assess the performance of current state-of-the-art density-functional theory for predicting the structure of such large and complex systems, where weak interactions such as dispersion or hydrogen bonds play a crucial role. For validation of the theoretical results, we employ experimental gas-phase ion mobility-mass spectrometry and IR spectroscopy. While unsolvated Ac-Ala19-Lys + H(+) will be shown to be a clear helix seeker, the structure space of Ac-Lys-Ala19 + H(+) is more complicated. Our first-principles structure-screening strategy using the dispersion-corrected PBE functional (PBE + vdW(TS)) identifies six distinctly different structure types competing in th...

ACS Medicinal Chemistry Letters, 2014

Since peptides are vital for cellular and pathogenic processes, much effort has been put into the... more Since peptides are vital for cellular and pathogenic processes, much effort has been put into the design of unnatural oligomers that mimic natural peptide structures, also referred to as foldamers. However, to enable the specific application of foldamers, a thorough characterization of their interaction profiles in native protein environments is required. We report here the application of phage display for the identification of suitable helical environments for a sequence comprising an alternating set of βand γ-amino acids. In vitro selected sequences show that an increase in the hydrophobic surface area at the helical interface as well as the incorporation of a polar Hbond donor functionality can significantly improve interhelical interactions involving backbone-extended amino acids. Thus, our data provide insight into the principles of the rational design of foldameric inhibitors for protein− protein interactions.

Journal of Cheminformatics, 2014

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C98S) in a cardiac TnI core structure (McTnI-ND 29 -Cys) did not affect the COOH-terminal conform... more C98S) in a cardiac TnI core structure (McTnI-ND 29 -Cys) did not affect the COOH-terminal conformation of TnI and preserved binding to TnT and TnC. McTnI-ND 29 -Cys purified from bacterial culture was fluorescently labeled with the Alexa Fluor 532 dye and used to reconstitute troponin complex. After verifying the ratio of fluorophore to protein conjugation by spectrophotometer and SDS-PAGE, Ca 2þ -titrations were performed for fluorescence intensity and polarization changes. The results demonstrated Ca 2þ regulated conformational/environmental changes as well as flexibility change in the COOH terminus of TnI. Further experiments are performed to measure the Ca 2þ -induced structural changes in reconstituted myofilaments to understand the function of TnI COOH terminal domain in calcium-regulation of muscle contraction.

Journal of Chemical Information and Modeling, 2015

Involved in numerous key biological functions, protein helix-helix interactions follow a well-def... more Involved in numerous key biological functions, protein helix-helix interactions follow a well-defined intermolecular recognition pattern. The characteristic structure of the α-helical coiled-coil allows for the specific randomization of clearly defined interaction partners within heteromeric systems. In this work, a rationally designed heterodimeric coiled-coil was used to investigate potential factors influencing the sequence selectivity in interhelical interactions.

Arteriosclerosis, Thrombosis, and Vascular Biology, 2014

Journal of the American Chemical Society, Jan 23, 2014

Ultraviolet photodissociation (UVPD) of gas-phase proteins has attracted increased attention in r... more Ultraviolet photodissociation (UVPD) of gas-phase proteins has attracted increased attention in recent years. This growing interest is largely based on the fact that, in contrast to slow heating techniques such as collision induced dissociation (CID), the cleavage propensity after absorption of UV light is distributed over the entire protein sequence, which can lead to a very high sequence coverage as required in typical top-down proteomics applications. However, in the gas phase, proteins can adopt a multitude of distinct and sometimes coexisting conformations, and it is not clear how this three-dimensional structure affects the UVPD fragmentation behavior. Using ion mobility-UVPD-mass spectrometry in conjunction with molecular dynamics simulations, we provide the first experimental evidence that UVPD is sensitive to the higher order structure of gas-phase proteins. Distinct UVPD spectra were obtained for different extended conformations of 11(+) ubiquitin ions. Assignment of the f...

Thrombosis and Haemostasis, 2014

The bleeding disorder von Willebrand disease (VWD) is caused by mutations of von Willebrand facto... more The bleeding disorder von Willebrand disease (VWD) is caused by mutations of von Willebrand factor (VWF), a multimeric glycoprotein essential for platelet-dependent primary haemostasis. VWD type 2A-associated mutations each disrupt VWF biosynthesis and function at different stages, depending on the VWF domain altered by the mutation. These effects cause considerable heterogeneity in phenotypes and symptoms. To characterise the molecular mechanisms underlying the specific VWF deficiencies in VWD 2A/IIC, IID and IIE, we investigated VWF variants with patient-derived mutations either in the VWF pro-peptide or in domains D3 or CK. Additionally to static assays and molecular dynamics (MD) simulations we used microfluidic approaches to perform a detailed investigation of the shear-dependent function of VWD 2A mutants. For each group, we found distinct characteristics in their intracellular localisation visualising specific defects in biosynthesis which are correlated to respective multimer patterns. Using microfluidic assays we further determined shear flow-dependent characteristics in polymer-platelet-aggregate formation, platelet binding and string formation for all mutants. The phenotypes observed under flow conditions were not related to the mutated VWF domain. By MD simulations we further investigated how VWD 2A/IID mutations might alter the ability of VWF to form carboxy-terminal dimers. In conclusion, our study offers a comprehensive picture of shear-dependent and shear-independent dysfunction of VWD type 2A mutants. Furthermore, our microfluidic assay might open new possibilities for diagnosis of new VWD phenotypes and treatment choice for VWD patients with shear-dependent VWF dysfunctions that are currently not detectable by static tests.

The Journal of Physical Chemistry B, 2008

Experimental and theoretical data demonstrate that sequences of heterochiral 2,3 -amino acids and... more Experimental and theoretical data demonstrate that sequences of heterochiral 2,3 -amino acids and a turninducing -dipeptide adopt hairpin-like structures in methanol. On the basis of extensive canonical and replica exchange MD simulations, we could transfer these findings to water as the solvent of physiological relevance. We show that rationally designed -peptides exhibit a higher folding tendency and a more robust hairpin structure formation in water compared with R-peptides. Furthermore, our designed scaffold enables the addition of a wide variety of functions without disrupting the structure. Since hairpins are often involved in protein interactions, the very stable hairpin-like fold of our designed -peptides might be used as a lead scaffold for the design of molecules that specifically modulate protein-protein interactions. This is demonstrated by application of this concept to the recognition of proline-rich sequences (PRS) by WW domains, an important interaction in cell signaling. We focus on the possibility to imitate the strands 2 and 3 of any WW domain as a minimal motif to recognize their target sequences PPXY. We conclude that rationally designed -peptide hairpins can serve as scaffolds not only to tackle PPII recognition but also to open up a way to influence a wide variety of protein-protein interactions.

The Journal of Physical Chemistry B, 2012

The cis peptide bond is a characteristic feature of turns in protein structures and can play the ... more The cis peptide bond is a characteristic feature of turns in protein structures and can play the role of a hinge in protein folding. Such cis conformations are most commonly found at peptide bonds immediately preceding proline residues, as the cis and trans states for such bonds are close in energy. However, isomerization over the high rotational barrier is slow.

Physical Biology, 2006

Peptoids of αand β-peptides (α-and β-peptoids) can be obtained by shifting the amino acid side ch... more Peptoids of αand β-peptides (α-and β-peptoids) can be obtained by shifting the amino acid side chains from the backbone carbon atoms of the monomer constituents to the peptide nitrogen atoms. They are, therefore, N-substituted poly-glycines and poly-β-alanines, respectively. Due to the substituted nitrogen atoms, the ability for hydrogen bond formation between peptide bonds gets lost. It may be very interesting to see whether such non-natural oligomers could be regarded as foldamers, which fold into definite backbone conformers. In this paper, we provide a complete overview on helix formation in αand β-peptoids on the basis of systematic theoretical conformational analyses employing the methods of ab initio molecular orbital (MO) theory. It can be shown that the αand β-peptoid structures form helical structures with both trans and cis peptide bonds despite the missing hydrogen bonds. Obviously, the conformational properties of the backbone are more important for folding than the possibility of hydrogen bonding. There are close relationships between the helices of α-peptoids and poly-glycine and poly-proline helices of α-peptides, whereas the helices of β-peptoids correspond to the well-known helical structures of β-peptides as, for instance, the 3 1 -helix of β-peptides with 14-membered hydrogen-bonded rings. Thus, αand β-peptoids enrich the field of foldamers and may be used as useful tools in peptide and protein design.

Journal of Thrombosis and Haemostasis, 2009

To avoid pathological platelet aggregation by von Willebrand factor (VWF), VWF multimers are regu... more To avoid pathological platelet aggregation by von Willebrand factor (VWF), VWF multimers are regulated in size and reactivity for adhesion by ADAMTS13-mediated proteolysis in a shear flow dependent manner. We examined if tensile stress in VWF under shear flow activates the VWF A2 domain for cleavage by ADAMTS13 using molecular dynamics simulations. We indeed observed stepwise unfolding of A2 and exposure of its deeply buried ADAMTS13 cleavage site. Interestingly, disulfide bonds in the adjacent and highly homologous VWF A1 and A3 domains obstruct their mechanical unfolding. We generated a full length mutant VWF featuring a homologous disulfide bond in A2 (N1493C and C1670S), in an attempt to lock A2 against unfolding. We find this mutant to feature ADAMTS13resistant behavior in vitro. Our results yield molecular-detail evidence for the force-sensoring function of VWF A2, by revealing how tension in VWF due to shear flow selectively exposes the A2 proteolysis site to ADAMTS13 for cleavage while keeping the folded remainder of A2 intact and functional. We find the unconventional 'knotted' Rossman fold of A2 to be the key to this mechanical response, tailored for regulating VWF size and activity. Based on our model we can explain the pathomechanism of some natural mutations in the VWF A2 domain that significantly increase the cleavage by ADAMTS13 without shearing or chemical denaturation, and provide with the cleavage-activated A2 conformation a structural basis for the design of inhibitors for VWF type 2 diseases.

The Journal of Organic Chemistry, 2005