Computer simulations of cyclic enkephalin analogues

Molecular dynamics simulations and energy minimization studies of cyclic enkephalin analogues incorporating retro-inverso modifications have been carried out. The dynamic trajectories are analyzed in terms of the relative mobility of the 14-membered rings, conformational transitions among equilibrium states, and hydrogen-bonding patterns. The cyclization of the molecules reduces the motion of the ring structures substantially. Time-correlated conformational transitions resulting in the reorientation of peptide units are observed. Hydrogen bonds form principally C7 structures. Because of the incorporation of retro-inverso residues, C6 and C8 structures are also formed. Starting conformations for energy minimizations were obtained from the molecular dynamics simulations and from a systematic search of the conformational space available to the molecules. Several minimum energy backbone and side-chain conformations were found for each analogue. The effect of retro-inverso residues on hydrogen-bonding patterns and backbone conformations is discussed.     

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.     

A three-dimensional model of the delta-opioid pharmacophore: comparative molecular modeling of peptide and nonpeptide ligands

A comparative molecular modeling study of delta-opioid ligands was performed under the assumption that potent peptide and nonpeptide agonists may have common three-dimensional (3D) arrangement of pharmacophore groups upon binding to the delta-receptor. Low-energy conformations of the agonists 7-spiroindanyloxymorphone (SIOM) and 2-methyl-4a-alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12a-alpha-octahydro-quinolino[2,3,3-g]isoquinoline (TAN-67), and a partial agonist oxomorphindole (OMI) were determined by high-temperature molecular dynamics (MD). A good spatial overlap was found for the pharmacophore groups of SIOM, TAN-67, and OMI, including the basic nitrogen, phenol hydroxyl, and two aromatic ring. Based on this overlap we proposed a 3D pharmacophore model for nonpeptide delta-opioid agonists with a distance of 7.0 +/- 1.3 A between the two aromatic rings and of 8.2 +/- 1.0 A between the nitrogen and phenyl ring. The potent and highly delta-opioid receptor selective agonist [(2S,3R)-TMT(1)]DPDPE, which shares global backbone constraints of the 14-membered disulfide cycle and a strong preference for the trans rotamer of the TMT(1) side chain, was chosen as a peptide template of the delta-opioid pharmacophore. Extensive MD simulations at 300 K with the AMBER force field were performed for [(2S,3R)-TMT(1)]DPDPE and the less potent [(2S, 3S)-TMT(1)]DPDPE analogue. Multiple MD trajectories were collected for each peptide starting from the x-ray structures of DPDPE and [L-Ala(3)]DPDPE and from models proposed in the literature. Low-energy MD conformations were filtered by the nonpeptide pharmacophore query and then directly superimposed with SIOM, OMI, and TAN-67. Two conformers of [(2S,3R)-TMT(1)]DPDPE that showed the best overlap with the nonpeptide pharmacophore (rms deviation 相似文献   

Peptides and Peptoids - A Systematic Structure Comparison

A systematic analysis of the conformational space of the basic structure unit of peptoids in comparison to the corresponding peptide unit was performed based on ab initio MO theory and complemented by molecular mechanics (MM) and molecular dynamics (MD) calculations both in the gas phase and in aqueous solution.The calculations show three minimum conformations denoted as C_7ß, a_D and a that do not correspond to conformers on the gas phase peptide potential energy hypersurface. The influence of aqueous solvation was estimated by means of continuum models. The MD simulations indicate the a_D form as the preferred conformation in solution both in cis and trans peptide bond orientations.     

A conformational comparison of two stereoisomeric cyclic dermorphin analogues employing NMR and computer simulations

In a continuation of our program to study the structure-activity relationship of peptide opiates, we report the conformational analysis of two cyclic tetrapeptides related to dermorphin--Tyr-c[D-Orn-Phe-Asp]-NH2 and Tyr-c[D-Asp-Phe-Orn]-NH2. These analogues have similar binding properties marked by a high selectivity for the mu-opioid receptors because of a drastic decrease in the affinity for the delta-opioid receptor. The conformational preferences of these analogues of dermorphin determined from proton nmr, molecular dynamics, and energy minimizations are quite similar. The constraint of the 13-membered ring formed from cyclization is quite evident from the conformational analysis. The constrained ring system acts as a template maintaining the relative orientation of the exocyclic tyrosine and side chain of phenylalanine. Two intramolecular hydrogen bonds measured for the D-Orn analogue in DMSO were disrupted upon the addition of water. For the D-Asp analogue, two intramolecular hydrogen bonds were found stable in DMSO and water. The global conformations of the two peptides determined from nuclear Overhauser effects did not change with the solvent titration. The difference in the hydrogen bonding within the 13-membered ring may account for the slight differences observed in the efficacy of the analogues at the mu-opioid receptors.     

Molecular dynamics study of iduronate ring conformation

Molecular dynamics (MD) simulations of the conformation of the iduronate ring in a methyl glycoside and as the central residue in a trisaccharide have been carried out. Separate simulations were carried out with initial ¹C₄, ²S₀, and ⁴C₁ iduronate ring conformations. Simulations were followed by observing the time development of the Cremer–Pople ring puckering parameters θ,?₂. Starting with chair geometries gave trajectories showing only ring oscillations close to the initial geometry. Simulations were performed with a ²S₀ starting geometry using explicit water and in vacuum with dielectric constants (ε) of 1 and 80, as well as with distance-dependent dielectric functions of 2r and 4r. In both the explicit water simulation and the vacuum (ε = 80) simulations, extensive pseudorotational motion was observed in which boat and twist-boat ring conformers interconvert. The overall range of ?₂2 variation in the trisaccharide was about half of that observed in the methyl glycoside. The Haasnoot procedure for calculating H-H coupling constants in saccharides was applied to structures obtained from MD trajectories. Using MD time averaged couplings along with experimental data allowed the relative fractions of chair and boat/twist-boat forms to be derived. © 1993 John Wiley & Sons, Inc.     

Temperature‐accelerated molecular dynamics gives insights into globular conformations sampled in the free state of the AC catalytic domain

The catalytic domain of the adenyl cyclase (AC) toxin from Bordetella pertussis is activated by interaction with calmodulin (CaM), resulting in cAMP overproduction in the infected cell. In the X‐ray crystallographic structure of the complex between AC and the C terminal lobe of CaM, the toxin displays a markedly elongated shape. As for the structure of the isolated protein, experimental results support the hypothesis that more globular conformations are sampled, but information at atomic resolution is still lacking. Here, we use temperature‐accelerated molecular dynamics (TAMD) simulations to generate putative all‐atom models of globular conformations sampled by CaM‐free AC. As collective variables, we use centers of mass coordinates of groups of residues selected from the analysis of standard molecular dynamics (MD) simulations. Results show that TAMD allows extended conformational sampling and generates AC conformations that are more globular than in the complexed state. These structures are then refined via energy minimization and further unrestrained MD simulations to optimize inter‐domain packing interactions, thus resulting in the identification of a set of hydrogen bonds present in the globular conformations. Proteins 2014; 82:2483–2496. © 2014 Wiley Periodicals, Inc.     

Asymmetric structure and domain binding interfaces of human tyrosyl‐tRNA synthetase studied by molecular dynamics simulations

Human tyrosyl‐tRNA synthetase (HsTyrRS) is composed of two structural modules: N‐terminal catalytic core and an EMAP II‐like C‐terminal domain. The structures of these modules are known, but no crystal structure of the full‐length HsTyrRS is currently available. An all‐atom model of the full‐length HsTyrRS was developed in this work. The structure, dynamics, and domain binding interfaces of HsTyrRS were investigated by extensive molecular dynamics (MD) simulations. Our data suggest that HsTyrRS in solution consists of a number of compact asymmetric conformations, which differ significantly by their rigidity, internal mobility, orientation of C‐terminal modules, and the strength of interdomain binding. Interfaces of domain binding obtained in MD simulations are in perfect agreement with our previous coarse‐grained hierarchical rotations technique simulations. Formation of the hydrogen bonds between R93 residue of the ELR cytokine motif and the residues A340 and E479 in the C‐module was observed. This observation supports the idea that the lack of cytokine activity in the full‐length HsTyrRS is explained by interactions between N‐modules and C‐modules, which block the ELR motif. Copyright © 2013 John Wiley & Sons, Ltd.     

Solution conformation of a pectic acid fragment by 1H-nmr and molecular dynamics

¹H-NMR and molecular dynamics simulations in vacuo and in water of (1 → 4)-α-D -galacturono-disaccharide were performed. The results of the molecular dynamics simulations showed that the molecule fluctuates between two conformations characterized by different values of torsion angles around the glycosidic linkage and two different intramolecular hydrogen bonds. When these conformations are extrapolated to a regular polymeric structure, they generate pectic acid compatible with a 2₁- or a right-handed 3₁-helix. © 1994 John Wiley & Sons, Inc.     

Influence of the disulfide bond configuration on the dynamics of the spin label attached to cytochrome c

A series of multi-nanosecond molecular dynamics (MD) simulations of wild-type cytochrome c and its spin-labeled variants with the methanethiosulfonate moiety attached at position C102 were performed (1) to elucidate the effect of the spin probe presence on the protein structure and (2) to describe the structure and dynamics of the spin-label moiety. Comparisons with the reference crystal structure of cytochrome c (PDB entry: 1YCC) indicate that the protein secondary structure is well preserved during simulations of the wild-type cytochrome c but slightly changed in simulations of the cytochrome c labeled at position C102. At the time scale covered in our simulations, the spin label exhibits highly dynamical behavior. The number of observed distinct conformations of the spin label moiety is between 3 and 13. The spin probe was found to form short-lived hydrogen bonds with the protein. Temporary hydrophobic interactions between the probe and the protein were also detected. The MD simulations directly show that the disulfide bond in the tether linking a spin probe with a protein strongly influence the behavior of the nitroxide group. The conformational flexibility and interaction with the protein are different for each of the two low energy conformations of the disulfide bond.     

Conformation dynamics of cyclic disulfides and selenosulfides in CXXC(U) (X = Gly,Ala) tetrapeptide redox motifs

Thioredoxin fold proteins often contain a Cys‐(Xxx)_n‐Cys(Sec) or CX_nC(U) motif, where the active cysteine (C) or selenocysteine (U) is bridged by X residues, which vary with protein function. The effect of the X residues on the conformation space of the oxidized disulfide and selenosulfide forms of the CXXC(U) motif has been investigated using molecular dynamics (MD) and density functional theory. Multi‐microsecond‐length MD simulations of the CGGC, CGAC, and CAGC cyclic peptides show that CGGC rings readily exchange between several conformations over the course of the simulation, but steric interactions with the methyl group of Ala limit the conformation space available to the cyclic peptide, especially for CGAC. The potential for the motif to be reduced, as measured by the energy of the lowest unoccupied molecular orbitals, is dependent upon the ring conformation. These results suggest that control of available conformations by the bridging residues and the protein tertiary structure may be important for defining the function of the CXXC motif. Theoretical ⁷⁷Se chemical shifts of the selenosulfide moiety are dependent upon the conformation and/or intramolecular Se···O interactions with the backbone carbonyl group of the C‐terminal U residue.     

Conformational preferences in diglycosyl disulfides: NMR and molecular modeling studies

The conformations of several β1→β1′ diglycosyl disulfides were investigated by NMR and computational methods. Experimental data, such as NOEs, proton–proton and proton–carbon-13 coupling constants, measured for solutions in DMSO, are in good agreement with values obtained by MD simulations in explicit DMSO. The disulfide torsion angles (C1–S–S–C1′) preferentially sample values close to either +90° or −90° (+g or −g) and appear as the main metric that determines the conformational behavior of these glycomimetics. There is more conformational freedom around the C1–S and C1′–S′ bonds (Φ and Ω torsions, respectively) and population cluster analysis allowed to identify up to four allowed conformational regions for each of the +g or −g forms. Population analysis of the hydroxylic group rotamers, based on proton–proton and proton–carbon-13 couplings as well as on calculated hydrogen bonding statistics, did not reveal any significant intramolecular hydrogen bonds in DMSO solution.     

Crystal structure,conformational analysis,and molecular dynamics of tetra-O-methyl-(+) -catechin

The structure of tetra-O-methyl- (+) -catechin has been determined in the crystalline state. Two independent molecules, denoted structure A and structure B, exist in the unit cell. Crystals are triclinic, space group P1, a = 4.8125(2) Å, b = 12.9148(8) Å, c = 13.8862(11) Å, α = 86.962(6) °, β = 89.120(5)°, γ = 88.044(5)°, Z = 2, D_c = 1.336 g cm^?3, R = 0.033 for 6830 observations. The heterocyclic rings of the crystal structures are compared to previous results for 8-bromotetra-O-methyl-(+)-catechin, penta-O-acetyl-(+)-catechin, and (?) -epicatechin. One of the two molecules has a heterocyclic ring conformation similar to that observed previously for (?)-epicatechin, and the other has a heterocyclic ring conformation similar to one predicted earlier in a theoretical analysis of dimers of (+)-catechin and (?) -epicatechin. Both structure A and structure B in the crystal have heterocyclic ring conformations that place the dimethoxyphenyl substituent at C(2) in the equatorial position. However, this heterocyclic ring conformation does not explain the proton nmr coupling constant measured in solution. Molecular dynamics simulations show an equatorial ? axial interconversion of the heterocyclic ring, which can explain the nmr results. © 1993 John Wiley & Sons, Inc.     

Transient hydrogen bonding in uniformly ¹³C,¹⁵N-labeled carbohydrates in water

We report NMR studies of transient hydrogen bonding in a polysaccharide (PS) dissolved in water without cosolvent at ambient temperature. The PS portion of the Escherichia coli O142 lipopolysaccharide is comprised of repeating pentasaccharide units of GalNAc (N-acetyl galactosamine), GlcNAc (N-acetyl glucosamine), and rhamnose in a 3:1:1 ratio, respectively. A 105-ns molecular dynamics (MD) simulation on one pentasaccharide repeat unit predicts transient inter-residue hydrogen bonds from the GalNAc NH groups in the PS. To investigate these predictions experimentally, the PS was uniformly ¹³C,¹⁵N enriched and the NH, carbonyl, C2, C4, and methyl resonances of the GalNAc and GlcNAc residues assigned using through-bond triple-resonance NMR experiments. Temperature dependence of amide NH chemical shifts and one-bond NH J couplings support that NH groups on two of the GalNAc residues are donors in transient hydrogen bonds. The remaining GalNAc and GlcNAc NHs do not appear to be donors from either temperature-dependent chemical shifts or one-bond NH J couplings. These results substantiate the presence of weak or partial hydrogen bonds in carbohydrates, and that MD simulations of repeating units in PSs provide insight into overall PS structure and dynamics. Published 2011 Wiley Periodicals, Inc. Biopolymers 97: 145–154, 2012.     

Molecular dynamics simulations of Ac-3Aib-Cage-3Aib-NHMe

Solvents play a stabilising role with the more stable conformations obtained in polar solvents than in vacuo. We investigate to what extent the structural propensities of the pentacyclo-undecane (PCU) cage polypeptide chain of the type Ac-3Aib-Cage-3Aib-NHMe are influenced in implicit water and in explicit solvents: methanol (MEOH), dimethyl sulphoxide (DMSO) and TIP3P water. The sampling of the α-helical conformations of the PCU cage polypeptide was investigated using the in-house modified PARM94 force-field parameters. Analysis of 50 ns molecular dynamics (MD) simulations revealed a tendency of the PCU cage polypeptide to assume bent structures, especially in polar solvents. The choice of solvents was designed to relate the simulations to physiological conditions. The individual amino-isobutyric acid residues predominantly sampled the right-handed and left-handed 3₁₀-helical conformations, indicating that the helical conformations are preferred in all four environments (in vacuo, MEOH, water and DMSO). Additionally, the 100 ns replica exchange MD (REMD) simulations of the PCU cage polypeptide in implicit water revealed more conformational variety present than in explicit solvents, and is more consistent with previous theoretical studies on the PCU cage residue. The present theoretical results may help in rationalising experimental results on these PCU cage polypeptides, and definitely show the importance of a dynamical approach for a correct interpretation and prediction of the conformational behaviour of the PCU cage molecules in different environments.     

Theoretical conformational analysis of a μ-selective cyclic opioid peptide analog

The allowed conformations of the μ-receptor-selective cyclic opioid peptide analog were determined using a grid search through the entire conformational space. Energy minimization of the 13-membered ring structure lacking the exocyclic Tyr¹ residue and the Phe³ side chain using the molecular mechanics program Maximin resulted in only four low-energy conformations. These four ring structures served as templates for a further energy minimization study with the Tyr¹ residue and Phe³ side chain added to the molecule. The results indicated that the Tyr¹ and Phe³ side chains enjoy considerable orientational freedom, but nevertheless, only a limited number of low-energy side-chain configurations were found. The obtained low-energy conformers are discussed in relation to various proposed models of the bioactive conformation of enkephalins and morphiceptin.     

β,γ-Diamino acid: an original building block for hybrid α/γ-peptide synthesis with extra hydrogen bond donating group

Using a β,γ-diamino acid, several small hybrid α/γ peptides have been synthesized and their conformations investigated through extensive NMR studies and molecular dynamics. A tripeptide and a tetrapeptide have thus shown several hydrogen bonds in solution, including a 13-membered ring involving the β-nitrogen.     

A molecular dynamics study of the 41-56 beta-hairpin from B1 domain of protein G.

The structural and dynamical behavior of the 41-56 beta-hairpin from the protein G B1 domain (GB1) has been studied at different temperatures using molecular dynamics (MD) simulations in an aqueous environment. The purpose of these simulations is to establish the stability of this hairpin in view of its possible role as a nucleation site for protein folding. The conformation of the peptide in the crystallographic structure of the protein GB1 (native conformation) was lost in all simulations. The new equilibrium conformations are stable for several nanoseconds at 300K (>10 ns), 350 K (>6.5 ns), and even at 450 K (up to 2.5 ns). The new structures have very similar hairpin-like conformations with properties in agreement with available experimental nuclear Overhauser effect (NOE) data. The stability of the structure in the hydrophobic core region during the simulations is consistent with the experimental data and provides further evidence for the role played by hydrophobic interactions in hairpin structures. Essential dynamics analysis shows that the dynamics of the peptide at different temperatures spans basically the same essential subspace. The main equilibrium motions in this subspace involve large fluctuations of the residues in the turn and ends regions. Of the six interchain hydrogen bonds, the inner four remain stable during the simulations. The space spanned by the first two eigenvectors, as sampled at 450 K, includes almost all of the 47 different hairpin structures found in the database. Finally, analysis of the hydration of the 300 K average conformations shows that the hydration sites observed in the native conformation are still well hydrated in the equilibrium MD ensemble.