Conformations Of Tetrapeptides Research Articles

Transferability of the Electrostatic Parameters of the Polarizable Gaussian Multipole Model.

Accuracy and transferability are the two highly desirable properties of molecular mechanical force fields. Compared with the extensively used point-charge additive force fields that apply fixed atom-centered point partial charges to model electrostatic interactions, polarizable force fields are thought to have the advantage of modeling the atomic polarization effects. Previous works have demonstrated the accuracy of the recently developed polarizable Gaussian multipole (pGM) models. In this work, we assessed the transferability of the electrostatic parameters of the pGM models with (pGM-perm) and without (pGM-ind) atomic permanent dipoles in terms of reproducing the electrostatic potentials surrounding molecules/oligomers absent from electrostatic parameterizations. Encouragingly, both the pGM-perm and pGM-ind models show significantly improved transferability than the additive model in the tests (1) from water monomer to water oligomer clusters; (2) across different conformations of amino acid dipeptides and tetrapeptides; (3) from amino acid tetrapeptides to longer polypeptides; and (4) from nucleobase monomers to Watson-Crick base pair dimers and tetramers. Furthermore, we demonstrated that the double-conformation fittings using amino acid tetrapeptides in the αR and β conformations can result in good transferability not only across different tetrapeptide conformations but also from tetrapeptides to polypeptides with lengths ranging from 1 to 20 repetitive residues for both the pGM-ind and pGM-perm models. In addition, the observation that the pGM-ind model has significantly better accuracy and transferability than the point-charge additive model, even though they have an identical number of parameters, strongly suggest the importance of intramolecular polarization effects. In summary, this and previous works together show that the pGM models possess both accuracy and transferability, which are expected to serve as foundations for the development of next-generation polarizable force fields for modeling various polarization-sensitive biological systems and processes.

Optimal transport technique to understand peptide conformations

Using Protein Data Bank (PDB), the distribution of backbone torsional angle for dipeptides and tripeptides has been obtained and analyzed in several past works. However, the more extended peptides distributions are difficult to obtain due to the data sparsity. In this paper, we introduce a technique based on Optimal Transport theory to understand peptide conformations. This technique renders a computational method to determine the multi-point distribution of the backbone torsional angles of the peptide. Applying this technique, we study tetrapeptide conformations, presenting a detailed analysis of tetrapeptides distributions composed of Ala and Gly amino acids, and compare it with PDB data. Our study shows that tetrapeptides such as AAAA, AAAG, AGAA, and GAAA prefer right-handed alpha-helix secondary structure formations and beta-turns in GGGG, GAGG, AAGG, and AAGA.

Systematic search of conformations of five tetrapeptides and a divide and conquer strategy for the predictions of peptide structures

Conformations of biomolecules are the basis for their property studies and the predictions of peptide structures are of high interest in life science but very difficult in practice. The potential energy surfaces of five tetrapeptides, GGGG, GVGG, GTGG, GGYG and GSDG, are thoroughly explored here by considering all combinations of their internal single bond rotamers. The structural features of all the important tetrapeptide conformers are analyzed in detail and are characterized with five hydrogen bond configurations. Close connections between the conformations of tetrapeptides and their constituting dipeptides are found. A method for finding all important tetrapeptide conformers by splicing the parent dipeptide conformations is deduced. The splicing method is validated to be both efficient and reliable for all the tetrapeptides examined. Application of the splicing method to pentaglycine provides results far better than the literature. It also yields conformations with characteristic secondary structures such as strands, helices, and turns which are highly populated in proteins. Further development of the splicing method is a promising way to find a reliable and efficient amino acid sequence based protein structure prediction method.

Three-Dimensional Structural Diversity-Oriented Peptidomimetics Based on the Cyclopropylic Strain

Conformationally restricted peptidomimetics comprising eight stereoisomeric scaffolds with three-dimensional structural diversity were designed based on the structural features of cyclopropane, that is, cyclopropylic strain, which mimic wide-ranging tetrapeptide conformations covering β-turns through β-strands. Stereoselective synthesis of the designed peptidomimetics led to the identification of nonpeptidic melanocortin-4 receptor ligands.

In-peptide synthesis of di-oxazolidinone and dehydroamino acid–oxazolidinone motifs as β-turn inducers

Small and easy-to-do mimetics of β-turns are of great interest to interfere with protein-protein recognition events mediated by β-turn recognition motifs. We propose a straightforward procedure for constraining the conformation of tetrapeptides lacking a pre-formed scaffold. According to the stereochemistry array, N-Ts tetrapeptides including Thr or PhSer (phenylserine) at the positions 2 or 3 gave rise in a single step to the sequences Oxd(2)-Oxd(3) or ΔAbu(2)-Oxd(3) (Oxd, oxazolidin-2-one; ΔAbu, 2,3-dehydro-2-aminobutyric). These pseudo-Pro residues displayed highly constrained ϕ, ψ, and χ dihedral angles, and induced clear β-turns or inverse turns of type I or II, as determined by extensive spectroscopic and computational analyses.

Accurate quantum chemical energies for tetrapeptide conformations: why MP2 data with an insufficient basis set should be handled with caution

High-level quantum chemical calculations have been carried out for biologically-relevant conformers of tetrapeptides. Our results indicate potential problems if the widely-applied MP2 approach is used in such situations with basis sets of insufficient size. Efficient alternatives are discussed.

Coexistence of Hydrogen‐Bonded Loop and Extended Tetrapeptide Conformations

The conformations of a protected tetrathiopeptide have been analysed by isotope labelling and two-dimensional infrared spectroscopy (2D-IR). It has been found that Boc-Ala-Gly(=S)-Ala-Aib-OMe in acetonitrile, as well as its oxopeptide analogue, can adopt a hydrogen-bonded loop conformation in coexistence with less restricted structures. The two types of conformations interconvert too quickly to be resolved on the nuclear magnetic resonance (NMR) timescale, but give rise to different cross peaks in two-dimensional infrared spectra. The hydrogen bond between the Boc terminal group and the amide proton of Aib can be broken by photoisomerisation of the thioamide bond.

A near linear-scaling smooth local coupled cluster algorithm for electronic structure

We demonstrate near linear scaling of a new algorithm for computing smooth local coupled-cluster singles-doubles (LCCSD) correlation energies of quantum mechanical systems. The theory behind our approach has been described previously, [J. Subotnik and M. Head-Gordon, J. Chem. Phys. 123, 064108 (2005)], and requires appropriately multiplying standard iterative amplitude equations by a bump function, creating local amplitude equations (which are smooth according to the implicit function theorem). Here, we provide an example that this theory works in practice: we show that our algorithm leads to smooth potential energy surfaces and yields large computational savings. As an example, we apply our LCCSD approach to measure the post-MP2 correction to the energetic gap between two different alanine tetrapeptide conformations.

A Resolution-Of-The-Identity Implementation of the Local Triatomics-In-Molecules Model for Second-Order Møller−Plesset Perturbation Theory with Application to Alanine Tetrapeptide Conformational Energies

In this work, we incorporate the resolution-of-the-identity (RI) approximation into the theoretical framework of the local triatomics-in-molecules (TRIM) second-order Møller-Plesset (MP2) perturbation theory model. The resultant model, RI-TRIM MP2, emerges as a robust fourth-order methodology that extends the regime of practical MP2 calculations. With RI-TRIM MP2, correlation energy corrections can easily be obtained for systems that contain more than 125 heavy atoms with a computational timing cost less than those of the prerequisite self-consistent field procedure and popular density functional theory (DFT) alternatives. In this work, the chemical performance of RI-TRIM MP2 is numerically assessed against untruncated RI-MP2 and DFT (B3LYP) in determining the relative energies of 27 different alanine tetrapeptide conformations at the cc-pVXZ (X = D, T, and Q) levels and the results are T → Q extrapolated to the complete basis set limit. As the quality of the basis set employed increases, we report a significant reduction in the error introduced by the RI-TRIM approximation; at the cc-pVDZ level, the root mean-square (RMS) relative error was found as 0.192 kcal/mol and is decreased to an almost negligible 0.040 kcal/mol at the T → Q extrapolated complete basis set limit. Basis set dependence was investigated by computing the RMS (max) deviations from the extrapolated RI-MP2/cc-pV(TQ)Z data set found as 0.377 (0.944) kcal/mol (MP2/cc-pVTZ) and 0.250 (0.591) kcal/mol (TRIM MP2/cc-pVTZ). These deviations are chemically significant when compared against the conformer energy differences, suggesting that to obtain reliably converged relative conformational energies, computations must be done using the cc-pVTZ and cc-pVQZ basis sets followed by extrapolation to the cc-pV(TQ)Z limit. The findings reported herein also provide the first computational evidence demonstrating that the TRIM model approaches exactness as the one-particle basis approaches completeness.

Accurate ab Initio Quantum Chemical Determination of the Relative Energetics of Peptide Conformations and Assessment of Empirical Force Fields

Correlated ab initio calculations have been carried out with a parallel version of the PSGVB electronic structure code to obtain relative energetics of a number of conformations of the alanine tetrapeptide. The highest level of theory utilized, local MP2 with the cc-pVTZ(−f) correlation-consistent basis set, has previously been shown to provide accurate conformational energies in comparison with experiment for a data set of small molecules. Comparisons with published and new canonical MP2 calculations on the alanine dipeptide are made. Results for ten gas-phase tetrapeptide conformations and a β-sheet dipeptide dimer are compared with 20 different molecular mechanics force field parametrizations, providing the first assessment of the reliability of these models for systems larger than a dipeptide. Comparisons are made with the LMP2/cc-pVTZ(−f) results, which are taken as a benchmark for the tetrapeptides. Statistical summaries with regard to energetics and structure are produced for each force field, and ...

Correlation of beta-bend conformations of tetrapeptides with their activities in CD4-receptor binding assays.

Conformational analysis, based on ECEPP (Empirical Conformational Energy Program for Peptides) using the chain build-up procedure, was applied to determine the low-energy conformations for a series of tetrapeptides. The tetrapeptides are components of larger peptides which have been found to bind to the CD4 receptor of monocytes. Several previous studies have implicated the tetrapeptide units investigated here as being critical to the biological activities of the full peptides. Five such tetrapeptides were studied: Ser-Ser-Asn-Tyr (from ribonuclease A), Thr-Thr-Asn-Tyr (from peptide T, known to block human immunodeficiency virus from attaching to CD4+ T cells), Thr-Ile-Asn-Tyr (from polio virus coat protein, which is less active than the other peptides in binding to CD4 receptors), Ser-Ser-Ala-Tyr (from the gp 120 coat protein of human immunodeficiency virus, a variant of the peptide T sequence, active in blocking viral attachment to CD4+ cells), and the tetrapeptide from an active synthetic pentapeptide, Asn-Thr-Lys-Tyr (from Asn-Thr-Lys-Tyr-Thr). Using a 7 kcal/mol cutoff, the low-energy conformations for each peptide were computed. Approximately 20,000 conformations were computed for each tetrapeptide. Residue probability profiles were determined for each tetrapeptide. All tetrapeptides except for the polio sequence showed flexibility in the sense that many low-energy conformations were possible. In previous studies, it was postulated that the critical tetrapeptide units would adopt conformations similar to the one observed in a segment of ribonuclease A, residues 22-25, a beta-bend, which is part of an octapeptide segment (residues 19-26) that is homologous to the sequence of peptide T.(ABSTRACT TRUNCATED AT 250 WORDS)

Conformational analysis of cyclic tetrapeptides by molecular mechanics calculations

Molecular mechanics calculations of the cyclic tetrapeptide ring system for the cis, trans, cis, trans amide bond sequences for cyclo tetraglycine and cyclo tetraalanine have been carried out. A systematic search of conformational space was carried out by using Still's RINGMAKER in an attempt to find the global minimum for each amide bond sequence. Ring system structures were optimized by using the BAKMOD program. A comparison of 11 experimentally determined cyclic tetrapeptide conformations with the lowest energy calculated conformations showed that only 4 of 11 known cyclic tetrapeptides adopted the lowest energy conformation. However, when the destabilization energy between cyclo tetraalanine and cyclo tetraglycine was calculated, 10 of the 11 experimentally determined conformations for cyclic tetrapeptides with alternating cis, trans, cis, trans amide bond sequences adopted the conformations with the least de‐stabilization energy. The relationship between the molecular mechanics calculations and empirical rules for predicting cyclic tetrapeptide conformations is discussed.

A catalogue of phi, psi and omega torsion angles for tetrapeptides in proteins.

This work examined the degree of consistency, over multiple occurrences in several proteins, of conformations of tetrapeptides. A data base of 114 proteins was taken from the Brookhaven Data Bank. The number of occurrences of every tetrapeptide in these proteins was counted. For each tetrapeptide which occurred more than 6 times all phi, psi and omega angles were calculated and averaged over the occurrences. Due to the limitations of the data base there were only 24 tetrapeptides in this category. This does not provide sufficient information for the extensive prediction of structures which are not homologous to those already in the data base but the effectiveness of structure prediction can be expected to increase with the size of the data base.