Predictable Conformational Diversity in Foldamers of Sugar Amino Acids.

A systematic conformational search was carried out for monomers and homohexamers of furanoid ß-amino acids: cis-(S,R) and trans-(S,S) stereoisomers of aminocyclopentane carboxylic acid (ACPC), two different aminofuranuronic acids (AFUα and AFUß), their isopropylidene derivatives (AFU(ip)), and the key intermediate ß-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 ß-amino acids show great variability: while hydrophobic cyclopentane (cis-ACPC)6 and hydrophilic (XylAFUα/ß)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/ß is conformationally compatible with ß-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: δN(NH), δC(α), δC(ß), δC', δH(NH), and δH(α)) were computed for the amino acid backbone conformers (α(L), ß(L), γ(L), δ(L), ε(L), α(D), γ(D), δ(D), and ε(D) [Perczel et al., J Am Chem Soc 1991, 113, 6256]) modeled by oligoalanine structures. Topological differences of the extended fold were investigated on single ß-strands, hairpins with type I and II ß-turns, as well as double- and triple-stranded ß-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 (δH(NH), δC', and δN(NH)) for backbone structure determination of the parent residue. Experimental δH(α), δC(α), and δC(ß) values retrieved from protein database are in good agreement with the relevant computed data in the case of the common backbone conformers (α(L), ß(L), γ(L), and ε(L)), even though neighboring residue effects were not accounted for. Experimental and computed ΔδH(α)-ΔδC(α), ΔδH(α)-ΔδC(ß), and ΔδC(α)-ΔδC(ß) 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 H(α), C(α), and C(ß) 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.

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 beta-turns. Both approaches prefer the same 6 out of the 36 ideally possible backbone folds. Polyproline II unit (t epsilonL t epsilonL), other elongated structures (c epsilonL t epsilonL, t epsilonL t alphaL and t epsilonL t gammaL), type VIa (t epsilonL c alphaL) and type I or III beta-turns (t alphaL t alphaL) 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.

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 beta-turn structures.

Vicinal disulfide turns.

The formation of a disulfide bond between adjacent cysteine residues is accompanied by the formation of a tight turn of the protein backbone. In nearly 90% of the structures analyzed a type VIII turn was found. The peptide bond between the two cysteines is in a distorted trans conformation, the omega torsion angle ranges from 159 to -133 degrees, with an average value of 171 degrees. The constrained nature of the vicinal disulfide turn and the pronounced difference observed between the oxidized and reduced states, suggests that vicinal disulfides may be employed as a 'redox-activated' conformational switch.