Ilona Hudáky

Solvation model induced structural changes in peptides. A quantum chemical study on Ramachandran surfaces and conformers of alanine diamide using the polarizable continuum model

Potential energy surfaces of the model peptide HCO‐L‐Ala‐NH2 were calculated using polarizable continuum model (PCM) for the description of aqueous solution at RHF/3‐21G, RHF/6‐31+G(d), and B3LYP/6‐31+G(d) levels of theory. Energy minima were optimized at all three levels as well as at B3LYP/PCM/6‐311++G(d,p) level of theory. Results were correlated to experimental data of protein structures retrieved from PDB SELECT. It is concluded that alanine residues of proteins are modeled better by PCM results than by gas‐phase calculations on the alanine diamide model (frequently called alanine dipeptide model). The currently available version of the PCM model implemented in Gaussian 03 provides a reasonable alternative to anticipate solvation effects without the computational costs of introducing explicit solvent molecules into the model system. Frequencies calculated at RHF/PCM/6‐31+G(d) and B3LYP/PCM/6‐31+G(d) levels of theory show high correlation; thus, RHF results have their own merit.

Vicinal disulfide bridge conformers by experimental methods and by ab initio and DFT molecular computations

A systematic comparison is made between experimental and computational data gained on vicinal disulfide bridges in proteins and peptides. Structural and stability data of ab initio and density functional theory (DFT) calculations on the model compound 4,5‐ditiaheptano‐7‐lactam and the model peptide HCOox‐[CysCys]NH2 at RHF/3‐21G*, B3LYP/6‐31+G(d), and B3LYP/6‐311++G(d,p) levels of theory are presented. The data on XxxCysCysYyy type amino acid sequence units retrieved from PDB SELECT, along with data on sequence units that have vicinal disulfide bridge, taken from the Brookhaven Protein Data Bank, are conformationally characterized. Amino acid backbone conformations, cis‐trans isomerism of the amide bond between the two cysteine residues, and ring puckering are studied. Ring puckers are characterized by their relation to the conformers of the parent 4,5‐ditiaheptano‐7‐lactam. Computational precision and accuracy are proved by frequency calculation and solvent model optimization on selected conformers. It is found that the ox‐[CysCys] unit is able to accept types I, II, VIa, VIb, and VIII β‐turn structures. Proteins 2004.

Peptide Models XXXVIII. Proline conformers from X-ray crystallographic database and from ab initio computations

Abstract A systematic comparison is made between experimental and computational data gained on l -proline in peptides. Data on 214 XPY type amino acid sequence units taken from the Cambridge Structural Database as well as ab initio calculations on the model peptide HCO- l -Pro-NH 2 at the 3-21G and 6-31+G(d) RHF levels of theory are presented. Cis – trans isomerism, backbone conformation and ring puckering are studied. Ring puckers are characterized by pseudorotational coordinates. A convenient nomenclature of conformers is introduced. Population data gained directly from statistics and derived from energy calculations are also discussed.

Generation and analysis of the conformational potential energy surfaces of N-acetyl-N-methyl-L-alanine-N'-methylamide. An exploratory ab initio study

Abstract N-methylation is a naturally occurring modification in small peptides, e.g. antibiotics that can effect the conformational preferences of the molecule as well as the ease of trans to cis isomerization of the involved peptide bond. In the present exploratory study we have calculated the potential energy surface of both N -acetyl- l -alanine- N ′-methylamide and N -acetyl- N -methyl- l -alanine- N ′-methylamide at the RHF/3-21G level of theory with a cis – trans or with a trans – trans peptide conformation. With respect to the non-methylated model system our results indicate that N-methylation reduces the number of observable backbone conformers in both amide configurations. The effect of methylation on the ease of trans to cis isomerization was assessed by calculating the energetics of the corresponding transition structures. An increase in the activation energies of the trans to cis isomerization of the relevant peptide bond was observed for the N-methylated moiety.

Ab initio analysis of the conformational changes of the prolyl-proline model peptide

Abstract For- l -Pro- l -Pro-NH2 is an ab initio model of the prolyl-proline sequence unit present in numerous peptides and proteins. Cis–trans isomerization of the peptide linkage is a crucial step in accessing the active conformation of several proline containing macromolecules. The present study focuses on the flexibility of the five-membered pyrrolidine ring, which is considered to help other conformational changes as well as cis–trans isomerization. Ring flexibility is characterized by the pseudorotational amplitude, A, and the phase angle, P. Calculations are carried out at the RHF/6-31+G(d) level of theory. The choice of method and level of theory is further supported by single point DFT calculations. In the course of NMR structure determination of peptides or proteins, proline residues present in the sequences need special attention. Because of the lack of an amide hydrogen, sequential assignment of proline is rather complicated. Furthermore, in solution state, peptide cis–trans isomers are almost always present. Ab initio study on the For- l -Pro- l -Pro-NH2 model is a useful tool to discover the structural characteristics of the prolyl-proline sequence unit.

Prolylproline unit in model peptides and in fragments from databases

The prolylproline sequence unit is found in several naturally occurring linear and cyclic peptides with immunosuppressive and toxic activity. Furthermore, Pro–Pro units are abundant in collagen, in ligand motifs binding to SH3 or WW domains, as well as in vital enzymes such as DNA glycosylase and thrombin. In all these sequence units a special role is dedicated to conformation in order to successfully fulfill the appropriate biological function. Therefore, a detailed analysis of the basic conformational properties of Pro–Pro is expected to reveal the versatile structural role of this sequence. PCM (polarizable continuum model) calculations on the basis of ab initio and density functional theory investigations using the model peptide HCO–L‐Pro–L‐Pro–NH2 are presented. Cis–trans isomerism, backbone conformation and ring puckering are studied. A systematic comparison is made to experimental data gained on L‐prolyl–L‐proline sequence units retrieved from the Protein Data Bank as well as from the Cambridge Structural Database. PCM data are in good agreement with high‐resolution X‐ray crystallography. Population data derived from energy calculations and those gained directly from statistics predict that 87% of the Pro–Pro sequence units adopt elongated structures, while 13% form β‐turns. Both approaches prefer the same 6 out of the 36 ideally possible backbone folds. Polyproline II unit (tϵLtϵL), other elongated structures (cϵL tϵL, tϵL tαL and tϵL tγL), type VIa (tϵL cαL) and type I or III β‐turns (tαL tαL) altogether describe 96% of the prolylproline sequences. In disordered proteins or domains, Pro–Pro sequence units may sample the various conformers and contribute to the segmental motions. Proteins 2008.

Peptide models XXXV. Protonated and deprotonated N-Formyl-l-histidinamide: an ab initio study on side-chain potential energy surfaces of all major backbone conformers

Abstract Charged forms of N -Formyl- l -histidinamide and ethylimidazole molecules were subjected to conformational analysis at the ab initio RHF/6-31G(d) level of theory. Side-chain potential energy surfaces, E = E bb ( χ 1 , χ 2 ), were calculated at the nine typical backbone conformations (bb=α L , α D , β L , γ L , γ D , δ L , δ D , e L and e D ) given by multidimensional conformational analysis (MDCA). Envisaged minima obtained from the topological analysis of E = E bb ( χ 1 , χ 2 ) surfaces and from MDCA were fully optimized. Electrostatic interaction between charged side-chain and polar peptide bonds is discussed. Stabilization energy was calculated for each conformer of N -Formyl- l -histidinamide and scored relative to the stabilization energy of other amino acids.

Predictable Conformational Diversity in Foldamers of Sugar Amino Acids

A systematic conformational search was carried out for monomers and homohexamers of furanoid β-amino acids: cis-(S,R) and trans-(S,S) stereoisomers of aminocyclopentane carboxylic acid (ACPC), two different aminofuranuronic acids (AFUα and AFUβ), their isopropylidene derivatives (AFU(ip)), and the key intermediate β-aminotetrahydrofurancarboxylic acid (ATFC). The stereochemistry of the building blocks was chosen to match that of the natural sugar amino acid (xylose and ribose) precursors (XylAFU and RibAFU). The results show that hexamers of cis-furanoid β-amino acids show great variability: while hydrophobic cyclopentane (cis-ACPC)6 and hydrophilic (XylAFUα/β)6 foldamers favor two different zigzagged conformation as hexamers, the backbone fold turns into a helix in the case of (cis-ATFC)6 (10-helix) and (XylAFU(ip))6 (14-helix). Trans stereochemistry resulted in hexamers exclusively with the right-handed helix conformation, (H12P)6, regardless of their polarity. We found that the preferred oligomeric structure of XylAFUα/β is conformationally compatible with β-pleated sheets, while that of the trans/(S,S) units matches with α-helices of proteins.

Local protein backbone folds determined by calculated NMR chemical shifts

NMR chemical shifts (CSs: δNNH, δCα, δCβ, δC′, δHNH, and δHα) were computed for the amino acid backbone conformers (αL, βL, γL, δL, εL, αD, γD, δD, and εD [Perczel et al., J Am Chem Soc 1991, 113, 6256]) modeled by oligoalanine structures. Topological differences of the extended fold were investigated on single β‐strands, hairpins with type I and II β‐turns, as well as double‐ and triple‐stranded β‐sheet models. The so‐called “capping effect” was analyzed: residues at the termini of a homoconformer sequence unit usually have different CSs than the central residues of an adequately long homoconformer model. In heteroconformer sequences capping effect ruins the direct applicability of several chemical shift types (δHNH, δC′, and δNNH) for backbone structure determination of the parent residue. Experimental δHα, δCα, and δCβ values retrieved from protein database are in good agreement with the relevant computed data in the case of the common backbone conformers (αL, βL, γL, and εL), even though neighboring residue effects were not accounted for. Experimental and computed ΔδHα‐ΔδCα, ΔδHα‐ΔδCβ, and ΔδCα‐ΔδCβ maps give qualitatively the same picture, that is, the positions of the backbone conformers relative to each other are very similar. This indicates that the Hα, Cα, and Cβ chemical shifts of alanine depend considerably on the backbone fold of the parent residue also in proteins. We provide tabulated CSs of the chiral amino acids that may predict the various structures of the residues.