Atomic charges for molecular dynamics calculations

Atomic charges obtained with the fit of the ab initio electrostatic potential suffers of several defects, for instance, chemical meaning is not insured. We have employed a method recently put forward for deriving atomic charges which addresses the issue of chemical meaning and conformational transferability to N,N-dibutylacetamide and ethylenediaminetetraacetate. The charges have been used in molecular dynamics calculations where the interaction with a metallic cation is considered. We found structural parameters for the complexes in good agreement with the available experimental results.     

Conformational analysis of six- and twelve-membered ring compounds by molecular dynamics

A molecular dynamics (MD)-based conformational analysis has been performed on a number of cycloalkanes in order to demonstrate the reliability and generality of MD as a tool for conformational analysis. MD simulations on cyclohexane and a series of methyl-substituted cyclohexanes were performed at temperatures between 400 and 1200 K. Depending on the simulation temperature, different types of interconversions (twist-boat–twist-boat, twist- boat–chair and chair–chair) could be observed, and the MD simulations demonstrated the expected correlation between simulation temperature and ring inversion barriers. A series of methyl-substituted 1,3- dioxanes were investigated at 1000 K, and the number of chair–chair interconversions could be quantitatively correlated to the experimentally determined ring inversion barrier. Similarly, the distribution of sampled minimum-energy conformations correlated with the energy-derived Boltzmann distribution. The macrocyclic ring system cyclododecane was subjected to an MD simulation at 1000 K and 71 different conformations could be sampled. These conformations were compared with the results of previously reported conformational analyses using stochastic search methods, and the MD method provided 19 out of the 20 most stable conformations found in the MM2 force field. Finally, the general performance of the MD method for conformational analysis is discussed.     

Local elevation: A method for improving the searching properties of molecular dynamics simulation

Summary The concept of memory has been introduced into a molecular dynamics algorithm. This was done so as to persuade a molecular system to visit new areas of conformational space rather than be confined to a small number of low-energy regions. The method is demonstrated on a simple model system and the 11-residue cyclic peptide cyclosporin A. For comparison, calculations were also performed using simulated temperature annealing and a potential energy annealing scheme. Although the method can only be applied to systems with a small number of degrees of freedom, it offers the chance to generate a multitude of different low-energy structures, where other methods only give a single one or few. This is clearly important in problems such as drug design, where one is interested in the conformational spread of a system.     

Spontaneous formation of annular structures observed in molecular dynamics simulations of polyglutamine peptides

Annular structures have been observed experimentally in aggregates of polyglutamine-containing proteins and other proteins associated with diseases of the brain. Here we report the observation of annular structures in molecular-level simulations of large systems of model polyglutamine peptides. A system of 24 polyglutamine chains 16 residues long at a concentration of 5 mM spontaneously formed large beta sheets which curved to form tube-like annular structures that resemble beta barrels. This work was accomplished by extending the PRIME model to polyglutamine. PRIME is an off-lattice, unbiased, intermediate-resolution protein model based on an amino acid representation of between three and seven united atoms depending on the residue being modeled. Our results are interesting not only because of the recent discovery of tubular protofibrils in experiments on aggregation of mutant huntingtin fragments containing expanded polyglutamine tracts but also because Perutz predicted that polyglutamine forms water filled nanotubes.     

Simulation of conformational transitions

Conformational transitions are essential for the functioning of many proteins, and understanding this dynamical behavior is a central goal in molecular biology. Computer simulations are playing an important role towards this aim by providing insights into how the conformational changes are induced, propagated and used. Popular methods for the simulation of conformational transitions will be reviewed, with a focus on atomistic molecular dynamics techniques for the calculation of transition pathways     

Molecular dynamics simulations of a nucleoside analogue of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid synthesized as a potential antiviral agent: Conformational studies in vacuum and in water

Conformational analysis of nucleosides may have direct applications to the structure–activity relationship (SAR) studies and in the design of new drug candidates. Although conformational analysis may be accessed in many different ways, in this work it was performed using molecular dynamics (MD) simulation in order to study the dynamic behavior of a nucleoside derivative of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, synthesized by our group as a potential antiviral agent. The MD simulation was carried out during 10 ns in vacuum and in a box of water at two different temperatures (i.e., 300 and 600 K) using the AMBER force field. The in vacuum MD simulation results are in agreement with the crystallographic structure and with the DFT calculations of the nucleoside, revealing the anti conformer as the more stable one. The simulation in water, however, shows that both conformers may exist at 300 K, the temperature of the in vivo and in vitro assays, revealing that both the syn and anti conformers should be considered in a MD simulation study of the inhibitor–enzyme complex. Simulations are also in agreement with the NOE experiment, which shows that the anti conformer is the preferential one in DMSO-d6 solution at 298 K.     

A molecular dynamics study of the pentacyclo-undecane cage amino acid tripeptide

In this paper, we report on the conformational profile of the pentacyclo-undecane (PCU) cage tripeptide carried out by molecular dynamics (MD) simulation using water as an explicit solvent. The MD solution phase studies carried on the model peptide analogues (A)=Ac–Ala–Ala–Ala–NHMe; (B)=Ac–Cage–Cage–Cage–NHMe; (C)=Ac–Ala–Cage–Ala–NHMe and (D)=Ac–Ala–Pro–Ala–NHMe, are used as a complimentary technique to the corresponding gas phase simulated annealing (SA) study previously carried out in our laboratory. No significant structural changes were observed over the MD trajectories. However, the results reported here provide further evidence that the (PCU) cage amino acid exhibits C_7eq, C_7aq, _R and _L conformations, and the theoretical results suggest that the PCU cage amino acid is a strong β-turn inducer. These results support the prediction that when the PCU cage residues are in the (i) and (i+2) positions, the β-turn can be extended in either direction to form anti-parallel β-pleated sheets, thereby forming the basis of the mechanism for the folding back of the chain in a cross-β-turn structure.     

Inhibitors of prolyl endopeptidase: Characterization of the pharmacophoric pattern using conformational analysis and 3D-QSAR

Summary A structure-activity study has been carried out on several compounds known as inhibitors of the serine protease prolyl endopeptidase. Conformational analysis has been done using different molecular mechanics methods such as molecular dynamics, or a randomized conformational search method. The conformers obtained were classified using geometric and energetic criteria. A pattern recognition analysis was done in order to divide conformers according to families. The resulting dominant families, for all compounds investigated, showed very similar geometric features. Based on the lowest energy conformers obtained after randomized conformational analysis, a 3D-QSAR model was established using the CoMFA approach. The validity of this model was verified by prediciting correctly the activity of other molecules not used in the construction of this model.     

Molecular dynamics simulations of ligand-induced backbone conformational changes in the binding site of the periplasmic lysine-, arginine-, ornithine-binding protein

The periplasmic lysine-, arginine-, ornithine-binding protein (LAOBP) traps its ligands by a large hinge bending movement between two globular domains. The overall geometry of the binding site remains largely unchanged between the open (unliganded) and closed (liganded) forms, with only a small number of residues exhibiting limited movement of their side chains. However, in the case of the ornithine-bound structure, the backbone peptide bond between Asp11 and Thr12 undergoes a large rotation. Molecular dynamics simulations have been used to investigate the origin and mechanism of this backbone movement. Simulations allowing flexibility of a limited region and of the whole binding site, with and without bound ligands, suggest that this conformational change is induced by the binding of ornithine, leading to the stabilisation of an energetically favourable alternative conformation.     

Molecular dynamics simulations of the isolated domain 1 of annexin I

Annexin molecules consist of a symmetrical arrangement of four domains of identical folds but very different sequences. Nuclear magnetic resonance (NMR) experiments on the isolated domains of annexin I in aqueous solution have indicated that domain 1 retains its native structure whereas domain 2 unfolds. Therefore these two domains constitute interesting models for comparative simulations of structural stability using molecular dynamics. Here we present the preliminary results of molecular dynamics simulations of the isolated domain 1 in explicit water at 300 K, using two different simulation protocols. For the first, domain 1 was embedded in a 46 ? cubic box of water. A group-based non-bonded cut-off of 9 ? with a 5–9 ? non-bonded switching function was used and a 2 fs integration step. Bonds containing hydrogens were constrained with the SHAKE algorithm. These conditions led to unfolding of the domain within 400 ps at 300 K. In the second protocol, the domain was embedded in a 62 ? cubic box of water. An atom-based non-bonded cut-off of 8–12 ? using a force switching function for electrostatics and a shifting function for van der Waals interactions were used with a 1 fs integration step. This second protocol led to a native-like conformation of the domain in accord with the NMR data which was stable over the whole trajectory (∼2 ns). A small, but well-defined relaxation of the structure, from that observed for the same domain in the entire protein, was observed. This structural relaxation is described and methodological aspects are discussed. Received: 10 May 1998 / Accepted: 4 August 1998 / Published online: 2 November 1998     

Structure-activity relationships of pyrethroid insecticides. Part 2. The use of molecular dynamics for conformation searching and average parameter calculation

Summary Molecular dynamics simulations have been performed on a number of conformationally flexible pyrethroid insecticides. The results indicate that molecular dynamics is a suitable tool for conformational searching of small molecules given suitable simulation parameters. The structures derived from the simulations are compared with the static conformation used in a previous study. Various physicochemical parameters have been calculated for a set of conformations selected from the simulations using multivariate analysis. The averaged values of the parameters over the selected set (and the factors derived from them) are compared with the single conformation values used in the previous study.     

Quantum dynamics of a system of coupled nonlinear oscillators: Spectral and information entropy‐based analysis

The quantum dynamics of the evolution of a system of a few coupled nonlinear oscillators is studied. The spectral entropy and the quantal information entropy, as well as their correlation functions, are computed and used to identify distinctive phases of the evolution. The two entropy functions lead to similar conclusions. It appears that adiabatic switching of the nonlinear interaction does not affect the nature of the short time dynamics but affects the dynamics over intermediate time scales. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Synthesis of the pentasaccharide repeating unit of the O-antigen of Escherichia coli O175 using one-pot glycosylations and its conformational analysis

Synthesis of a pentasaccharide repeating unit of the cell wall O-antigenic polysaccharide of enteroaggregative Escherichia coli O175 has been achieved using one-pot, three components [1+2+2] block glycosylations. The intermediate steps were good yielding and satisfactory stereoselectivity was observed in the glycosylations. The synthesized pentasaccharide was subjected to conformational analysis in aqueous environment using 2D ROESY NMR spectral analysis in conjugation with molecular dynamics (MD) simulation technique.     

Estimation and analysis of the rheological properties of a perfluoropolyether through molecular dynamics simulation

Equilibrium and non-equilibrium molecular dynamics simulations of a perfluoropolyether C₈F₁₈O₄ are reported using an atomistic interaction potential. The bulk rheological properties of the perfluoropolyether are investigated through molecular dynamics simulations as a function of both temperature and shear rate. The effect of molecular structure on viscosity is explored in detail. The rotational relaxation time is reported as a function of temperature. Structural properties, including the mean-square end-to-end chain length, the mean-square radius of gyration of chains, and the distribution functions of bond lengths, bond angles, and bond torsional angles are collected and analyzed as functions of shear rate. After an initial plateau, both mean-square end-to-end chain length and mean-square radius of gyration decrease monotonically with increasing shear rate. The behaviors of the rheological and structural properties are explained through an analysis of the individual contributions due to bond stretching, bond bending, and bond torsion, as well as both intramolecular and intermolecular non-bonded interactions. A further analysis is possible through a meticulous breakdown of each contribution into a specific type of mode; e.g., the total bond stretching is comprised of CC, CO, and CF bond stretching terms. In this way, one can relate the shear viscosity to the specific chemical structure of C₈F₁₈O₄.     

Theoretical investigations on the interactions of glucokinase regulatory protein with fructose phosphates

Glucokinase (GK) plays a critical role in maintaining glucose homeostasis in the human liver and pancreas. In the liver, the activity of GK is modulated by the glucokinase regulatory protein (GKRP) which functions as a competitive inhibitor of glucose to bind to GK. Moreover, the inhibitory intensity of GKRP–GK is suppressed by fructose 1-phosphate (F1P), and reinforced by fructose 6-phosphate (F6P). Here, we employed a series of computational techniques to explore the interactions of fructose phosphates with GKRP. Calculation results reveal that F1P and F6P can bind to the same active site of GKRP with different binding modes, and electrostatic interaction provides a major driving force for the ligand binding. The presence of fructose phosphate severely influences the motions of protein and the conformational space, and the structural change of sugar phosphate influences its interactions with GKRP, leading to a large conformational rearrangement of loop2 in the SIS2 domain. In particular, the binding of F6P to GKRP facilitates the protruding loop2 contacting with GK to form the stable GK–GKRP complex. The conserved residues 179–184 of GKRP play a major role in the binding of phosphate group and maintaining the stability of GKRP. These results may provide deep insight into the regulatory mechanism of GKRP to the activity of GK.     

Identify promising IKK-β inhibitors: A docking-based 3D-QSAR study combining molecular design and molecular dynamics simulation

Inhibitor of nuclear factor kappa B kinase subunit beta (IKK-β), a specific regulator of nuclear factor-κB (NF-κB), is considered a valid target to design novel drugs to treat rheumatoid arthritis, glomerulonephritis and various cancers. In this study, in order to design and then identify promising compounds targeting IKK-β, a series of reported IKK-β inhibitors were used to develop 3D-QSAR models. Docking-based and minimization-based poses were generated for model construction. CoMSIA model #8 based on docking poses was selected due to its satisfactory internal and external validation results and the sufficient information delivery capability. After a contour map analysis, 41 new designs were depicted based on a graphical design scheme and 25 of them were assessed as eligible for screening. Compound 21MX007 has aroused our attention for its both competitive QSAR-prediction and docking-scoring result. Detailed docking interactions of 21MX007-protein complex were investigated via a deep analysis of docking results and a comparative molecular dynamics simulation. Strong interactions and an extra hydrogen bond which echoes the H-bond requirements of substituent acquired from the design scheme were observed. From MD analysis, 21MX007-protein system was tested. The system was proved to have good stability in terms of a downward trend of RMSD and Rg values and a continuous and stable H-bond interaction and a lower average binding free energy. Thus, compound 21MX007 was successfully identified as a promising IKK-β inhibitor.     

Coupling overall rotations with modal dynamics

 We consider a model for protein dynamics in which only certain collective, global motions are allowed. These directions are given by the slowest harmonics modes, as given in the reference frame of the protein. Furthermore, the latter is allowed to rotate and translate in response to interactions with other molecules. The model is obtained by projecting the (averaged) Newton equations onto this set of harmonic modes. We show that the subsequent homogenization of the time scales allows time steps one order of magnitude larger than the standard ones. This homogenization is also shown to be a necessary ingredient in order to get meaningful statistics of the trajectory. Received: 3 July 2000 / Accepted: 15 September 2000 / Published online: 21 December 2000     

Impact of Stable Protein-protein Interaction on Protein Conformational Space

Backbone dihedral angle based clustering approach was applied to investigate the effect of protein complexation on backbone conformational space and the effect on protein dynamics. Three representative enzyme-inhibitor complexes and their comprised proteins were used as models for small-and moderate-sized globular proteins to compare available backbone conformational space before and after complexation. Microsecond time scale molecular dynamic simulations were generated to ensure sufficient statistics. The result suggests that stable protein-protein interactions lead to redistribution of protein backbone mobility and restriction of the protein backbone conformational space, especially for short time scale motions. Surprisingly, these effects are found to be uncorrelated with protein-protein interaction surface. Consistent with many experimental and computational observations, our results indicate that both induced-fit and conformational selection models play roles in stable protein complexation process, with the dominant role being different for different protein complexes.