Novel algorithms for searching conformational space

Summary The modelling of biological molecules by molecular dynamics is beset by a range of problems. The most important of these is the multiple-minima problem. The deep metastable minima can cause difficulties in proper equilibration of a molecular system and result in the simulated system being trapped in a long-lived metastable state. One way to overcome these problems is to re-engineer the Newtonian Rules in order to more efficiently search conformational space. Re-engineering of the Newtonian Rules implies a redesign of the physical laws arising from them. This is done in various ways by the RUSH, Hybrid Monte Carlo and PEACS algorithms. This paper explores applications of these algorithms, and compares them to a traditional molecular dynamics method.     

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.     

Sampling conformational hyperspace: Techniques for improving completeness

Summary Three new strategies for sampling the conformation space accessible to a series of structurally diverse, flexible molecules are defined and compared to samples obtained using a fixed-grid torsion angle sampling strategy. A set of 28 potent inhibitors of angiotensin converting enzyme selected by Mayer et al. [J. Comput.-Aided Mol. Design, 1 (1987) 3] and the unrestricted active-site model proposed by Waller et al. [to be published] are used to produce a realistic experimental setting. We modified our Constrained Search algorithm [Dammkoehler et al., J. Comput.-Aided Mol. Design, 3 (1989) 3] to support these new sampling strategies, performing a series of 64 simulations (search experiments) and generating a large set of sterically allowed conformations. In each experiment, we systematically vary the internal torsion angles in each molecule using one of the sampling strategies. The common orientations of preselected functional groups thought to represent those dominating the interaction with the enzyme and presented by the set of molecules are classified and recorded for each experiment. Pairwise distances between groups are used to characterize the geometry of the common orientations. The results of each experiment, represented by a set of distance values, are compared and combined to evaluate the completeness of the conformational sampling. While no pure strategy or single search experiment was found to be adequate to fully explore the set of common sterically allowed conformations, a new sampling technique, called adaptive radial sampling, is shown to be significantly more complete than the commonly used fixed grid sampling.     

Structure and dynamics of water at water|Pt interface as seen by molecular dynamics computer simulation

Five molecular dynamics computer simulations were performed to study the structural and dynamical properties of water next to uncharged and charged Pt surfaces. The results show that the structure of a water layer adsorbed on the metal surface is very sensitive to the details of the water–metal potential. While patches of short-living hexagonal ice-like structure are observed in the adsorbed water layer next to the uncharged Pt(111) surface, a square lattice solid-like structure is seen for the layer on top of the uncharged Pt(100) surface. The orientational ordering for the following two layers of water next to uncharged Pt is displaying a preference towards the orientations that are characteristic of hexagonal ice-I, while water is liquid-like in these layers. In the presence of a high value external electric field water reorients and undergoes a layering transition.     

Conformational search by potential energy annealing: Algorithm and application to cyclosporin A

Summary A major problem in modelling (biological) macromolecules is the search for low-energy conformations. The complexity of a conformational search problem increases exponentially with the number of degrees of freedom which means that a systematic search can only be performed for very small structures. Here we introduce a new method (PEACS) which has a far better performance than conventional search methods.To show the advantages of PEACS we applied it to the refinement of Cyclosporin A and compared the results with normal molecular dynamics (MD) refinement. The structures obtained with PEACS were lower in energy and agreed with the NMR parameters much better than those obtained with MD. From the results it is further clear that PEACS samples a much larger part of the available conformational space than MD does.     

Recent advances in molecular dynamics simulation towards the realistic representation of biomolecules in solution

Coupled advances in empirical force fields and classical molecular dynamics simulation methodologies, combined with the availability of faster computers, has lead to significant progress towards accurately representing the structure and dynamics of biomolecular systems, such as proteins, nucleic acids, and lipids in their native environments. Thanks to these advances, simulation results are moving beyond merely evaluating force fields, displaying expected structural fluctuations, or demonstrating low root-mean-squared deviations from experimental structures and now provide believable structural insight into a variety of processes such as the stabilization of A-DNA in mixed water and ethanol solution or reversible β-peptide folding in methanol. The purpose of this overview is to take stock of these recent advances in biomolecular simulation and point out some common deficiencies exposed in longer simulations. The most significant methodological advances relate to the development of fast methods to properly treat long-range electrostatic interactions, and in this regard the fast Ewald methods are becoming the de facto standard. Received: 9 April 1998 / Accepted: 21 May 1998 / Published online: 13 August 1998     

A molecular mechanism of P-loop pliability of Rho-kinase investigated by molecular dynamic simulation

Rho-kinase is a leading player in the regulation of cytoskeletal events involving smooth muscle contraction and neurite growth-cone collapse and retraction, and is a promising drug target in the treatment of both vascular and neurological disorders. Recent crystal structure of Rho-kinase complexed with a small-molecule inhibitor fasudil has revealed structural details of the ATP-binding site, which represents the target site for the inhibitor, and showed that the conserved phenylalanine on the P-loop occupies the pocket, resulting in an increase of protein–ligand contacts. Thus, the P-loop pliability is considered to play an important role in inhibitor binding affinity and specificity. In this study, we carried out a molecular dynamic simulation for Rho-kinase–fasudil complexes with two different P-loop conformations, i.e., the extended and folded conformations, in order to understand the P-loop pliability and dynamics at atomic level. A PKA–fasudil complex was also used for comparison. In the MD simulation, the flip-flop movement of the P-loop conformation starting either from the extended or folded conformation was not able to be observed. However, a significant conformational change in a long loop region covering over the P-loop, and also alteration of ionic interaction-manner of fasudil with acidic residues in the ATP binding site were shown only in the Rho-kinase–fasudil complex with the extended P-loop conformation, while Rho-kinase with the folded P-loop conformation and PKA complexes did not show large fluctuations, suggesting that the Rho-kinase–fasudil complex with the extended P-loop conformation represents a meta-stable state. The information of the P-loop pliability at atomic level obtained in this study could provide valuable clues to designing potent and/or selective inhibitors for Rho-kinase. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Forging of nicotine for the effective management of diabetic wounds: A hybrid of scaffold hopping and molecular dynamics simulation approaches

Diabetic wound (DW) is a huge threat to the health care community and is always challenging to treat. The main biochemical culprits in DW recalcitrance are elevated inflammatory mediators, proteases, cell proliferation and migration suppressors, anti-angiogenic factors, and bacterial infections. In this scenario, using a scaffold to target important factors at each stage of pathogenesis can accelerate the healing process. Many shreds of evidence disclosed the role of nicotine scaffold in handling inflammation, infection, proliferation, migration, and angiogenesis. All these factors made us forge nicotine by employing a scaffold hopping approach. The hops were then subjected to molecular docking and binding free energy calculations against Matrix metallopeptidase 9, Glycogen synthase kinase 3 beta, Tumor necrosis factor alpha, MurC and ParE enzymes. Gratifyingly, molecule H1 was found to possess significant inhibitory activity against the selected receptors as evidenced by their high negative glide score and binding energy. Furthermore, 100 ns of molecular dynamics simulation studies (MD) was performed for the five H1/4XCT, H1/5F95, H1/2AZ5, H1/4C13 and H1/4MOT complexes to get insight into the binding modes and stability. The MD results showed significant stability as evidenced by the low conformational changes of the H1 with the chosen receptors. Hence, H1 might be a druggable candidate in the therapeutic management of DW. However, further research is strongly recommended to advance the drug into the therapeutic pipeline.     

A molecular dynamics simulation study of peptide deformylase from Leptospira interrogans complex：Exploring the closing mechanism of the substrate pocket

To explore the closing mechanism of the substrate pocket,we perform a 16,000 ps molecular dynamics simulation separately on the ligand-free and actinonin-bound peptide deformylase from Leptospira interrogans.Our results show that the CD-loop, hydrophilic inhibitor and hydrophobic cluster are necessary for the formation of semi-open conformation,and Tyr71 plays an important role in mediating the movements of CD-loop.The average MD structure of the actinonin-bound LiPDF complex approaches to the crystal structure.These are consistent with experiment very well.     

Communication performance of d -meshes in molecular dynamics simulation

Communication algorithms, tailored for molecular dynamics simulation on d-meshes, are evaluated in terms of communication efficiency. It has been shown elsewhere that d-meshes are better than other regular topologies, e.g., hypercubes and standard toroidal 4-meshes, when compared in their diameter and average distance among nodes. Collective communication is needed in molecular dynamics simulation for the distribution of coordinates and calculation and distribution of new energies. We show that both collective communication patterns used in molecular dynamics can be efficiently solved with congestion-free algorithms for all-to-all communication based on store-and-forward routing and routing tables. Our results indicate that d-meshes compete with hypercubes in parallel computers. Therefore d-meshes can also be used as a communication upgrade of existing molecular dynamics simulation platforms and can be successfully applied to perform fast molecular dynamics simulation.     

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.     

IBIsCO: a molecular dynamics simulation package for coarse-grained simulation

IBIsCO is a parallel molecular dynamics simulation package developed specially for coarse-grained simulations with numerical potentials derived by the iterative Boltzmann inversion (IBI) method (Reith et al., J Comput Chem 2003, 24, 1624). In addition to common features of molecular dynamics programs, the techniques of dissipative particle dynamics (Groot and Warren, J Chem Phys 1997, 107, 4423) and Lowe-Andersen dynamics (Lowe, Europhys Lett 1999, 47, 145) are implemented, which can be used both as thermostats and as sources of friction to compensate the loss of degrees of freedom by coarse-graining. The reverse nonequilibrium molecular dynamics simulation method (Müller-Plathe, Phys Rev E 1999, 59, 4894) for the calculation of viscosities is also implemented. Details of the algorithms, functionalities, implementation, user interfaces, and file formats are described. The code is parallelized using PE_MPI on PowerPC architecture. The execution time scales satisfactorily with the number of processors.     

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.     

Molecular dynamics simulations of cyclosporin A: The crystal structure and dynamic modelling of a structure in apolar solution based on NMR data

Summary The conformation of the immunosuppressive drug cyclosporin A (CPA), both in apolar solution and in crystalline state, has been studied by computer simulation techniques. Three molecular dynamics (MD) simulations have been performed: one modelling the crystal structure and two modelling the structure in apolar solution, using a restrained MD approach in which data from nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy are taken into account. The simulation of the crystalline state (MDC) concerns a system of 4 unit cells containing 16 cyclosporin A molecules and 22 water molecules, which is simulated using crystalline periodic boundary conditions. The simulations modelling the apolar solvent conformation (MDS) concern one isolated cyclosporin A molecule. In these simulations an extra term in the interatomic potential function is used, which forces the molecule to satisfy a set of 57 atom-atom distance constraints originating from nuclear Overhauser effects (NOEs) obtained from NMR spectroscopy and one distance constraint deduced from IR spectroscopy.From a comparison of the results of the crystal simulation to those of the X-ray experiment in terms of structure, atomic fluctuations, hydrogen bond pattern, etc., it is concluded that the force field that is used yields an adequate representation of crystalline cyclosporin A. Secondly, it is shown that the dynamic modelling technique that is used to obtain a structure in a polar solution from NMR distance information works well. Starting from initial conformations which have a root mean square difference of 0.14 nm both distance restrained MD simulations converge to the same final solution structure. A comparison of the crystal structure of cyclosporin A and the one in apolar solution shows that there are significant differences. The overall difference in atomic positions is 0.09 nm for the C_x atoms and 0.17 nm for all atoms. In apolar solution, the molecule is slightly more bent and the side chains of 1 MeBmt and 10 MeLeu adopt a different conformation.Abbreviations MeBmt (4R)-4[(E)-2-butenyl]-4-methyl-l-Threonine - MD Molecular dynamics - EM Energy minimization - MDC Molecular dynamics simulation of the crystal - MDS1 Restrained molecular dynamics simulation to obtain the structure in solution starting from the crystal structure - MDS2 Like MDS1, but starting from the SMS structure - SMS Proposed structure in solution, obtained by model building - XRAY An X-ray structure - CPA Cyclosporin A - NMR Nuclear magnetic resonance spectroscopy - NOE Nuclear Overhauser enhancement - MDS1 Mean simulated structure obtained by averaging over the time period 20–40 ps of the MDS1 simulation - MDS2 Mean simulated structure obtained by averaging over the time period 10–30 ps of the MDS2 simulation - Mean simulated structure obtained by averaging over the time period 7–15 ps and over the 16 asymmetric units in the computational box of the MDC simulation.     

Performance evaluation of functionalized ordered mesoporous silica for VOCs adsorption by molecular dynamics simulation

Volatile organic compounds (VOCs) are growing pollutants now that cause the serious environmental pollution and threaten human health. The functionalized ordered mesoporous silica (FOMS) has attracted considerable attention in adsorbing VOCs. In this paper, the molecular dynamics simulation was used to simulate the adsorption performance of FOMS on VOCs (acetone, ethyl acetate and toluene). After simulating different pore sizes (2 nm, 3 nm and 4 nm) adsorption performances of ordered mesoporous silica (OMS) on VOCs, OMS with a pore size of 4 nm was selected to further study the influence of functional groups (vinyl, methyl, and phenyl). The following law was obtained: the saturated adsorption capacities of vinyl-functionalized OMS (V-FOMS) to acetone, ethyl acetate and toluene were 3.045 mmol.g^?1, 2.568 mmol.g^?1 and 1.976 mmol.g^?1 respectively; the saturated adsorption capacities of methyl-functionalized OMS (M-FOMS) to acetone, ethyl acetate and toluene were 2.798 mmol.g^?1, 2.312 mmol.g^?1 and 1.698 mmol.g^?1 respectively; the saturated adsorption capacities of phenyl-functionalized OMS (P-FOMS) to acetone, ethyl acetate and toluene were 2.124 mmol.g^?1, 1.941 mmol.g^?1 and 1.539 mmol.g^?1 respectively. These results show that the adsorption ability of FOMS for different adsorbates follows the sequence of acetone > ethyl acetate > toluene. Furthermore, the interaction between functional groups (vinyl, methyl and phenyl) in FOMS and VOCs was explored. It is found that the interaction between different functional groups and adsorbates is different (interaction energy effect). This interaction energy effect promotes FOMS to better adsorb VOCs. This work would provide fundamental understanding and guidance for the development of novel adsorption materials for the adsorption of VOCs.     

Molecular dynamics simulation of the water|nitrobenzene interface

The structure and dynamics of the neat water|nitrobenzene liquid|liquid interface are studied at 300 K using molecular dynamics computer simulations. The water is modeled using the flexible SPC potential, and the nitrobenzene is modeled using an empirically determined nitrobenzene potential energy function. Although nitrobenzene is a polar liquid with a large dielectric constant, the structure of the interface is similar to other water|non-polar organic liquid interfaces. Among the main structural features we describe are an enhancement of interfacial water hydrogen bonds, the specific orientation of water dipoles and nitrobenzene molecules, and a rough surface that is locally sharp. Surface roughness is also characterized dynamically. The dynamics of molecular reorientation are shown to be only mildly modified at the interface. The effect due to the polarizable many-body potential energy functions of both liquids is investigated and is found to affect only mildly the above results.     

Dielectric relaxation in water–cholesterol mixture cluster: molecular dynamics simulation

Molecular dynamics (MD) studies of the cluster composed of cholesterol (C₂₇H₄₅OH) and water molecules are presented. We have investigated several dynamical quantities of cholesterol as a function of its concentration in the mixture cluster and the temperature. The main attention was focused on the temperature and concentration dependence of the calculated total dipole moment autocorrelation function and dielectric loss of the cluster.     

Molecular dynamics simulation of the aggregation of colloidal particles

The spontaneous time evolution of systems containing N colloidal particles (N = 12, 24, 100) in a spherical cell of volume V at a constant volume fraction φ=0.1 was studied by a molecular dynamics method in the NVT ensemble. The starting velocities of the particles are allocated according to the Maxwell distribution at T=273 K.

Pairwise interaction of the particles was specified by molecular, electrostatic and elastic forces. The changes in the potential energy of the systems were calculated during the establishment of dynamic equilibrium. Coagulation takes place at sufficiently high values of the Hamaker constant. The value of the coefficient of Brownian diffusion, which is calculated from the half-time of coagulation, is found to be close to the known value for aqueous dispersions. The inclusion of electrostatic forces prevents coagulation.

The results obtained are in agreement with those obtained using theories of aggregate formation. Some structural characteristics of aggregates and stable systems are discussed.     

基于分子对接的thanatin与NDM-1分子动力学模拟研究

耐碳青霉烯类抗生素的超级细菌给人类健康带来了严重威胁,其所携带的金属 β-内酰胺酶编码基因是耐药性的主要来源。NDM-1作为其中传播最广、活性最强的 β-内酰胺酶,其抑制剂的研发刻不容缓。具有广谱作用的抗菌肽thanatin对NDM-1展现出了较好的抑制效果,但抑制机理并不清楚。本文使用HPEPDOCK与Rosetta FlexPepDock服务器,将thanatin与NDM-1进行了分子对接,并使用Desmond软件包对对接模型进行了分子动力学模拟。结果表明,thanatin与NDM-1活性中心的Zn2+ 并无直接相互作用,而作为竞争性抑制剂结合于NDM-1的活性口袋,阻止抗生素分子进入活性口袋与Zn2+ 结合,从而抑制NDM-1的水解活性。本文为研发有效的NDM临床抑制剂探索了可行的方法。     

Molecular orientation of monododecyl pentaethylene glycol at water/air and water/oil interfaces. A molecular dynamics computer simulation study

With a molecular dynamics computer simulation we investigated the dynamic properties of a monododecyl pentaethylene glycol (C₁₂E₅) molecule adsorbed at air/water and oil/water interfaces. In these simulations we investigated the molecular orientation of the surfactant molecules in detail. At the air/water interface the maximum of the C₁₂ chain tilt angle distribution measured with respect to the water surface is about 50°. This result is in fairly good agreement with neutron reflection experiments of monododecyl glycol ethers at the air/water interface. At the oil/water interface no significant changes were detected in the molecular orientation. We found that at equilibrium oil molecules penetrate into the hydrophobic monododecyl layer, this was also found by neutron reflection studies of the interactions between C₁₂E₅ and dodecane. The observed oil penetration results in an increase in the surface area per surfactant molecule. Received: 16 July 1999/Accepted in revised form: 28 August 1999