Conformation Of Dipeptides Research Articles

The preferred conformation of dipeptides in the context of biosynthesis

Globular proteins are folded polypeptide structures comprising stretches of secondary structures (helical (α- or 310 helix type), polyproline helix or β-strands) interspersed by regions of less well-ordered structure ("random coil"). Protein fold prediction is a very active field impacting inte alia on protein engineering and misfolding studies. Apart from the many studies of protein refolding from the denatured state, there has been considerable interest in studying the initial formation of peptides during biosynthesis, when there are at the outset only a few residues in the emerging polypeptide. Although there have been many studies employing quantum chemical methods of the conformation of dipeptides, these have mostly been carried out in the gas phase or simulated water. None of these conditions really apply in the interior confines of the ribosome. In the present work, we are concerned with the conformation of dipeptides in this low dielectric environment. Furthermore, only the residue types glycine and alanine have been studied by previous authors, but we extend this repertoire to include leucine and isoleucine, position isomers which have very different structural propensities.

Molecular dynamics and quantum chemical studies of solvent effects on cyclo glycylglycine and glycylalanine dipeptides

Hydrogen bond (H-bond) interactions between the two cyclo dipeptides, cyclo(glycyl-glycine) (CGG) and cyclo(glycyl-alanine) (CGA), and water have been studied using molecular dynamics (MD) and quantum chemical methods. The MD studies have been carried out on CGG and CGA in water using fixed charge force field (AMBER ff03) for over 10 ns with a MD time step of 2 fs. The results of this study show that the solvation pattern influences the conformations of the cyclo dipeptides. Following molecular simulations, post Hartree–Fock and density functional theory methods have been used to explore the molecular properties of the cyclo dipeptides in gaseous and aqueous phase environments. The self-consistent reaction field theory has been used to optimise the cyclopeptides in diethyl ether (ϵ = 4.3) and water (ϵ = 78.5), and the solvent effects have been analysed. A cluster of eight water molecules leads to the formation of first solvation shell of CGG and CGA and the strong H-bonding mainly contributes to the interaction energies. The H-bond interactions have been analysed by the calculation of electron density ρ(r) and its Laplacian ▽2ρ(r) at bond critical points using atoms in molecules theory. The natural bond orbital analysis was carried out to reveal the nature of H-bond interactions. In the solvated complexes, the keto carbons registered the maximum NMR chemical shifts.

Molecular dynamics simulations and density functional theory studies of NALMA and NAGMA dipeptides

Classical molecular dynamics (MD) simulations using fixed charged force field (AMBER ff03) and density functional theory method using the M05-2X/6-31G∗∗ level of theory have been used to investigate the plasticity of the hydrogen bond formed between dipeptides of N-Acetyl-Leucine-MethylAmide (NALMA), N-Acetyl-Glycine-MethylAmide (NAGMA), and vicinity of water molecules at temperature of 300 K. We have noticed that 2–3 water molecules contribute to change in the conformations of dipeptides NAGMA and NALMA. The self-assembly of 11 water molecules leads to the formation of water bridge at vicinity of the dipeptides and it constrain the conformations of dipeptides. We have found that the energy balance between breaking of the C = O…H–N H bonds and the formation of the C = O…H–O (wat) H bonds may be one of the determining factors to control the dynamics of the folding process of protein molecules.

Comprehensive Conformational Studies of Five Tripeptides and a Deduced Method for Efficient Determinations of Peptide Structures

Thorough searches on the potential energy surfaces of five tripeptides, GGG, GYG, GWG, TGG, and MGG, were performed by considering all possible combinations of the bond rotational degrees of freedom with a semiempirical and ab initio combined computational approach. Structural characteristics of the obtained stable tripeptide conformers were carefully analyzed. Conformers of the five tripeptides were found to be closely connected with conformers of their constituting dipeptides and amino acids. A method for finding all important tripeptide conformers by optimizing a small number of trial structures generated by suitable superposition of the parent amino acid and dipeptide conformers is thus proposed. Applying the method to another five tripeptides, YGG, FGG, WGG, GFA, and GGF, studied before shows that the new approach is both efficient and reliable by providing the most complete ensembles of tripeptide conformers. The method is further generalized for application to larger peptides by introducing the breeding and mutation concepts in a genetic algorithm way. The generalized method is verified to be capable of finding tetrapeptide conformers with secondary structures of strands, helices, and turns, which are highly populated in larger peptides. This show some promise for the proposed method to be applied for the structural determination of larger peptides.

Efficient exploration of reaction paths via a freezing string method

The ability to efficiently locate transition states is critically important to the widespread adoption of theoretical chemistry techniques for their ability to accurately predict kinetic constants. Existing surface walking techniques to locate such transition states typically require an extremely good initial guess that is often beyond human intuition to estimate. To alleviate this problem, automated techniques to locate transition state guesses have been created that take the known reactant and product endpoint structures as inputs. In this work, we present a simple method to build an approximate reaction path through a combination of interpolation and optimization. Starting from the known reactant and product structures, new nodes are interpolated inwards towards the transition state, partially optimized orthogonally to the reaction path, and then frozen before a new pair of nodes is added. The algorithm is stopped once the string ends connect. For the practical user, this method provides a quick and convenient way to generate transition state structure guesses. Tests on three reactions (cyclization of cis,cis-2,4-hexadiene, alanine dipeptide conformation transition, and ethylene dimerization in a Ni-exchanged zeolite) show that this "freezing string" method is an efficient way to identify complex transition states with significant cost savings over existing methods, particularly when high quality linear synchronous transit interpolation is employed.

Simulation of the β‐ to α‐sheet transition results in a twisted sheet for antiparallel and an α‐nanotube for parallel strands: Implications for amyloid formation

α-sheet has been proposed to be the main constituent of the toxic amyloid intermediate. Molecular dynamics simulations on proteins known to be involved in amyloid diseases have demonstrated that β-sheet can, under certain conditions, spontaneously convert to α-sheet via ββ→α(R)α(L) peptide-plane flipping. Using torsion-angle driving to simulate this flip the transition has been investigated for parallel and antiparallel sheets. Concerted and sequential flipping processes were simulated, the former allowing direct calculation of helical parameters. For antiparallel sheet, the strands tend to splay apart during the transition. This can be understood by consideration of the geometry of repeating dipeptide conformations. At the end of the transition antiparallel α-sheet is slightly twisted, comprising gently curving strands. In parallel sheet, the strands maintain identical conformations and stay hydrogen bonded during the transition as they curl up to suggest a hitherto unseen structure, the multi-helix α-nanotube. Intriguingly, the α-nanotube has some of the characteristics of the parallel β-helix, a single-helix structure also implicated in amyloid. Unlike the β-helix, α-nanotube formation could involve identical strands aligning with each other in register as in most amyloids.

Water-Mediated Conformations of the Alanine Dipeptide as Revealed by Distributed Umbrella Sampling Simulations, Quantum Mechanics Based Calculations, and Experimental Data

An exhaustive umbrella sampling simulation of the alanine dipeptide in solution is reported. The presence of stable Y conformations in solution is assessed by both quantum calculations and experimental data from X-ray and NMR protein-solved structures available in the protein coil library. The agreement between experimental and simulation Ramachandran plots of the dipeptide in solution is excellent. A suitable explanation of the stabilization of the Y conformation mediated by water for the alanine dipeptide is discussed on the basis of Car-Parrinello MD calculations of the dipeptide in water.

Conformational preferences, experimental and theoretical vibrational spectra of cyclo(Gly–Val) dipeptide

The theoretical conformational analysis of cyclic dipeptide, cyclo(glycine–valine), which has anticancer activity, has been performed by molecular mechanics method, in order to examine the energetically optimal conformational states. The relative positions of the side chain residues of the stable conformations of dipeptide were obtained. The obtained geometry of the most stable conformation of the cyclo(Gly–Val) was optimized using DFT method at B3LYP/6-31++G(d,p) level of theory. Afterwards dimeric forms of the dipeptide were formed and energetically preferred conformations of dimers were investigated using the same method and the same level of theory. The experimental IR and micro-Raman spectra of solid cyclo(Gly–Val) were reported for the first time. The vibrational normal modes and associated wavenumbers, IR intensities and Raman activities of the monomeric and dimeric forms of the dipeptide were calculated using DFT method at B3LYP/6-31++G(d,p) level of theory and the results were compared with the experimental data. The total energy distributions (TED) of the vibrational modes were calculated by using Scaled Quantum Mechanical (SQM) analysis. Vibrational assignment was performed on the basis of calculated total energy distribution (TED) of the modes.

Conformational analysis and vibrational spectroscopic investigation of l-proline–tyrosine ( l-Pro–Tyr) dipeptide

In this study the conformational properties of the drug based dipeptide l-proline– l-tyrosine (Pro–Tyr) in its monomeric and dimeric forms, have been investigated by molecular mechanic and ab initio calculations. The energy calculations on Pro–Tyr dipeptide as a function of side chains torsion angles, enable us to determine their energetically preferred conformations. One-hundred and eight possible conformations of Pro–Tyr dipeptide have been investigated by conformational analysis and the low energy conformations of dipeptide have been determined by using the Ramachandran maps. Afterwards, the geometrical parameters of obtained stable conformations were used as starting parameters for quantum chemical calculations. The molecular structure of Pro–Tyr dipeptide, in the ground electronic state (in vacuum) was optimized by density functional theory method with B3LYP functional and using 6-31G(d,p) and 6-31++G(d,p) basis sets. The dimeric forms of the dipeptide were also formed and energetically preferred conformations of dimers were investigated using the same method and the same level of theory by using 6-31G(d,p) basic set. The fundamental vibrational wavenumbers, IR intensities and Raman activities of the global conformation of monomeric and dimeric forms of the dipeptide were calculated and compared with the experimental vibrational spectra of solid Pro–Tyr dipeptide. The total energy distributions (TED) of the vibrational modes were calculated by using Scaled Quantum Mechanical (SQM) analysis. Vibrational assignment was performed on the basis of calculated total energy distribution (TED) of the modes.

Polarization-Angle-Scanning Two-Dimensional Spectroscopy: Application to Dipeptide Structure Determination

Coherent two-dimensional optical spectroscopy based on a heterodyne-detected stimulated photon echo measurement technique requires four ultrashort pulses whose pulse-to-pulse delay times, wavevectors, and frequencies are experimentally controllable variables. In addition, the polarization directions of the four radiations can also be arbitrarily adjusted. We show that the polarization-angle-scanning two-dimensional spectroscopy can be of effective use to selectively suppress either all the diagonal peaks or a cross-peak in a given two-dimensional spectrum. Theoretical relationships between the transition dipole vectors of a given pair of coupled modes or quantum transitions and the polarization angle configuration making the corresponding cross-peak vanish are established. Here, to shed light into the underlying principles of the polarization-angle-scanning two-dimensional spectroscopy, we considered the amide I vibrations of various isotope-labeled dipeptide conformers and show that one can selectively suppress a cross-peak by properly controlling the polarization angle of a chosen beam among them. Once the relative directions of the amide I transition dipole vectors are determined using the polarization-angle-scanning technique theoretically proposed here, they can serve as a set of constraints for determining structures of model peptides. The present work demonstrates that the polarization-controlled two-dimensional vibrational or electronic spectroscopy can provide invaluable information on intricate details of molecular structures.

Solvation Effect on the Conformations of Alanine Dipeptide: Integral Equation Approach

We present an implicit solvent model based on the extended reference interaction site model (XRISM) integral equation theory, which is a molecular theory of solvation. The solvation free energy is composed of additive potentials of mean force (PMF) of various functional groups. The XRISM theory is applied to determine the PMF of each group in water and NaBr electrolyte solutions. The method has been coupled to Brownian dynamics (BD) and is illustrated here on alanine dipeptide. The results of the method are compared with those obtained by explicit water simulations and other popular implicit solvent models for detailed discussion. The comparison of our model with other methods indicates that the intramolecular correlation and the solvation structure influence the stability of the PII and αR conformers. The results of NaBr electrolyte solutions show that the concentration of electrolyte also has a substantial effect on the favored conformations.

Synthesis and conformational analysis of bicyclic extended dipeptide surrogates.

Regio- and diastereoselective reactions of a homoproline enolate enable the synthesis of novel extended dipeptide surrogates. Bicyclic carbamate 9 and fused beta-lactam scaffold 11 were prepared from L-pyroglutamic acid via substrate-controlled electrophilic azidation. Synthesis of orthogonally protected hexahydropyrrolizine, hexahydropyrrolizinone, and hexahydropyrroloazepinone dipeptide surrogates relied on allylation of proline derivative 5, followed by Curtius rearrangement to introduce the N-terminal carbamate group. A total of six azabicycloalkane derivatives were evaluated for conformational mimicry of extended dipeptides by a combination of X-ray diffraction and molecular modeling. Analysis of putative backbone dihedral angles and N- to C-terminal dipeptide distances indicate that compounds (alpha'S)-14b and 21 approximate the conformation of dipeptides found in beta-sheets, while tripeptide mimic 28 is also highly extended in the solid state. Structural data suggest that ring size and relative stereochemistry have a profound effect on the ability of these scaffolds to act as beta-strand mimetics and should inform the design of related conformational probes.

Conformational analysis and vibrational spectroscopic investigation of L-alanyl-L-glutamine dipeptide

In this study conformational behavior of anticancer chemotherapy dipeptide Ala-Gln and its dimers have been investigated by molecular mechanic and ab-initio calculations. The calculations on Ala-Gln dipeptide as a function of side chain torsion angles, enable us to determine their energetically preferred conformations. The relative positions of the side chain residues of the stable conformations of dipeptide were obtained, depending on the obtained conformational analysis results. The lowest energy conformation of the dipeptide has been determined by using the Ramachandran maps (Biopolymers6(1963), 1494;J. Mol. Biol.7(1963), 95) and compared with the quantum chemical ab-initio results. The geometry optimization, vibrational wavenumbers and intensity calculations of Ala-Gln dipeptide were carried out with theGaussian03program by using DFT with B3LYP functional and 6-31++G(d,p) basis set. The IR (4000–400 cm−1) and Raman spectra of the Ala-Gln dipeptide have been reported in solid phase, and compared with the theoretical vibrational data.

Conformational analysis and vibrational spectroscopic investigation of L-alanyl-L-glutamine dipeptide

In this study conformational behavior of anticancer chemotherapy dipeptide Ala-Gln and its dimers have been investigated by molecular mechanic and ab-initio calculations. The calculations on Ala-Gln dipeptide as a function of side chain torsion angles, enable us to determine their energetically preferred conformations. The relative positions of the side chain residues of the stable conformations of dipeptide were obtained, depending on the obtained conformational analysis results. The lowest energy conformation of the dipeptide has been determined by using the Ramachandran maps (Biopolymers 6 (1963), 1494; J. Mol. Biol.7 (1963), 95) and compared with the quantum chemical ab-initio results. The geometry optimization, vibrational wavenumbers and intensity calculations of Ala-Gln dipeptide were carried out with the Gaussian03 program by using DFT with B3LYP functional and 6-31

Calculations of intermode coupling constants and simulations of amide I, II, and III vibrational spectra of dipeptides

Amide I, II, and III vibrations of polypeptides are important marker modes whose vibrational spectra can provide critical information on structure and dynamics of proteins in solution. The extent of delocalization and vibrational properties of amide normal mode can be described by the amide local mode frequencies and intermode coupling constants between a pair of amide local modes. To determine these fundamental quantities, the previous Hessian matrix reconstruction method has been generalized here and applied to the density functional theory results for various dipeptide conformers. The calculation results are then used to simulate IR absorption, vibrational circular dichroism, and 2D IR spectra of dipeptides. The relationships between dipeptide backbone conformations and these vibrational spectra are discussed. It is believed that the present computational method and results will be of use to quantitatively simulate vibrational spectra of complicated polypeptides beyond simple dipeptides

Extensive conformational searches of 13 representative dipeptides and an efficient method for dipeptide structure determinations based on amino acid conformers

Conformations of peptides are the basis for their property studies and the predictions of peptide structures are highly important in life science but very complex in practice. Here, thorough searches on the potential energy surfaces of 13 representative dipeptides by considering all possible combinations of the bond rotational degrees of freedom are performed using the density functional theory based methods. Careful analyses of the conformers of the 13 dipeptides and the corresponding amino acids reveal the connections between the structures of dipeptide and amino acids. A method for finding all important dipeptide conformers by optimizing a small number of trial structures generated by suitable superposition of the parent amino acid conformations is thus proposed. Applying the method to another eight dipeptides carefully examined by others shows that the new approach is both highly efficient and reliable by providing the most complete ensembles of dipeptide conformers and much improved agreements between the theoretical and experimental IR spectra. The method opens the door for the determination of the stable structures of all dipeptides with a manageable amount of effort. Preliminary result on the applicability of the method to the tripeptide structure determination is also presented. The results are the first step towards proving Anfinsen's hypothesis by revealing the relationships between the structures of the simplest peptide and its constituting amino acids. It implies that the structures of peptides are not only determined by their amino acid sequences, but also closely linked with the amino acid conformations.

Solid-State and Solution-Phase Conformations of Pseudoproline-Containing Dipeptides

The conformations of 14 threonine-derived pseudoproline-containing dipeptides (including four d-allo-Thr derivatives) have been investigated by NMR. In solution, the major conformer observed for all dipeptides is that in which the amide bond between the pseudoproline and the preceding amino acid is cis. For dipeptides in which the N-terminus is protected, the ratio of cis- to trans-conformers does not depend significantly on the side chain of the N-terminal amino acid, or the stereochemistry of the Thr residue. However, for dipeptides bearing a free N-terminus, there are significant differences in the ratios of cis- to trans-conformers depending on the side chain present. Three dipeptides were crystallized and their X-ray structures determined. In two cases, (benzyloxycarbonyl (Cbz)-Val-Thr(ΨMe,Mepro)-OMe and Cbz-Val-Thr(ΨMe,Mepro)-OH), the dipeptides adopt a trans-conformation in the solid state, in contrast to the structures observed in solution. In the third case, (9-fluorenylmethoxycarbonyl (Fmoc)-Val-d-allo-Thr(ΨMe,Mepro)-OH), a cis-amide geometry is observed. These structural differences are attributed to crystal-packing interactions.

Conformational Preferences and pKa Value of Cysteine Residue

The conformational preferences of the Cys dipeptides with thiol and thiolate groups (Ac-Cys-NHMe and Ac-Cys (-)-NHMe, respectively) and the apparent (i.e., macroscopic) p K a value of the Cys dipeptide have been studied at the hybrid density functional B3LYP/6-311++G(d,p)//B3LYP/6-31+G(d) level with the conductor-like polarizable continuum model in the gas phase and in water. The hydrogen bonds and/or favorable interactions between the backbone and the thiol group of the side chain resulted in the different conformational preferences of the Cys and Cys (-) dipeptides from those of the Ala dipeptide in the gas phase and in water, although the preferred conformations of the Cys dipeptide are in part similar to those of the Ala dipeptide. In particular, the interactions between the thiolate group and the backbone amide groups appear to play a role in stabilizing the alpha- or 3 10-helical conformations for the Cys (-) dipeptide in the gas phase and in water. The p K a value of the Cys residue is estimated to be 8.58 at 25 degrees C using the statistically weighted free energies of all feasible conformations for the Cys and Cys (-) dipeptides in the gas phase and solvation free energies, which is consistent with the observed values of 8.3 and 8.22 +/- 0.16.

Exploring the accuracy of relative molecular energies with local correlation theory

Local coupled-cluster singles–doubles theory (LCCSD) is a theorist’s attempt to captureelectron–electron correlation in a fast amount of time and with chemical accuracy. Manyof the difficult computational hurdles have been navigated over the last twentyyears, including how to construct a linear scaling algorithm and how to producesmooth potential energy surfaces. Nevertheless, there remains the question ofjust how accurate a local correlation model can be, and what are the chemicallimits within which local models are largely applicable. Here, we investigate howaccurately can LCCSD approximate full CCSD for cases of atomization energies,isomerization energies, conformational energies, barrier heights and electron affinities. Ourconclusion is that LCCSD computes relative energies that are correct to within1–2 kcal mol−1 of the CCSD energy using relatively aggressive cutoffs and over a broad range of differentmolecular environments—alkane isomers, dipeptide conformations, Diels–Alder transitionstates and electron attachment in charge delocalized systems. These findings should pushthe reach of local correlation applications into new research terrain, includingmolecules on metal cluster surfaces or perhaps even metal–molecule–metal clusters.

Using quantum mechanics to improve estimates of amino acid side chain rotamer energies

Amino acid side chains adopt a discrete set of favorable conformations typically referred to as rotamers. The relative energies of rotamers partially determine which side chain conformations are more often observed in protein structures and accurate estimates of these energies are important for predicting protein structure and designing new proteins. Protein modelers typically calculate side chain rotamer energies by using molecular mechanics (MM) potentials or by converting rotamer probabilities from the protein database (PDB) into relative free energies. One limitation of the knowledge-based energies is that rotamer preferences observed in the PDB can reflect internal side chain energies as well as longer-range interactions with the rest of the protein. Here, we test an alternative approach for calculating rotamer energies. We use three different quantum mechanics (QM) methods (second order Møller-Plesset (MP2), density functional theory (DFT) energy calculation using the B3LYP functional, and Hartree-Fock) to calculate the energy of amino acid rotamers in a dipeptide model system, and then use these pre-calculated values in side chain placement simulations. Energies were calculated for over 36,000 different conformations of leucine, isoleucine, and valine dipeptides with backbone torsion angles from the helical and strand regions of the Ramachandran plot. In a subset of cases these energies differ significantly from those calculated with standard molecular mechanics potentials or those derived from PDB statistics. We find that in these cases the energies from the QM methods result in more accurate placement of amino acid side chains in structure prediction tests.