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.     

Molecular dynamics study of catanionic bilayers composed of ion pair amphiphile with double-tailed cationic surfactant

The physical stability of catanionic vesicles is important for the development of novel drug or DNA carriers. For investigating the mechanism by which catanionic vesicles are stabilized, molecular dynamics (MD) simulation is an attractive approach that provides microscopic structural information on the vesicular bilayer. In this study, MD simulation was applied to investigate the bilayer properties of catanionic vesicles composed of an ion pair amphiphile (IPA), hexadecyltrimethylammonium-dodecylsulfate (HTMA-DS), and a double-tailed cationic surfactant, ditetradecyldimethylammonium chloride (DTDAC). Structural information regarding membrane elasticity and the organization and conformation of surfactant molecules was obtained based on the resulting trajectory. Simulation results showed that a proper amount of DTDAC could be used to complement the asymmetric structure between HTMA and DS, resulting in an ordered hydrocarbon chain packing within the rigid membrane observed in the mixed HTMA-DS/DTDAC system. The coexistence of gel and fluid phases was also observed in the presence of excess DTDAC. MD simulation results agreed well with results obtained from experimental studies examining mixed HTMA-DS/DTDAB vesicles.     

Effects of ionic strength on SAXS data for proteins revealed by molecular dynamics simulations

The combination of small-angle X-ray solution scattering (SAXS) experiments and molecular dynamics (MD) simulations is now becoming a powerful tool to study protein conformations in solution at an atomic resolution. In this study, we investigated effects of ionic strength on SAXS data theoretically by using MD simulations of hen egg white lysozyme at various NaCl concentrations from 0 to 1 M. The calculated SAXS excess intensities showed a significant dependence on ion concentration, which originates from the different solvent density distributions in the presence and absence of ions. The addition of ions induced a slow convergence of the SAXS data, and a ～20 ns simulation is required to obtain convergence of the SAXS data with the presence of ions whereas only a 0.2 ns simulation is sufficient in the absence of ions. To circumvent the problem of the slow convergence in the presence of ions, we developed a novel method that reproduces the SAXS excess intensities with the presence of ions from short MD trajectories in pure water. By applying this method to SAXS data for the open and closed forms of transferrin at 1 M ion concentration, the correct form could be identified by simply using short MD simulations of the protein in pure water for 0.2 ns.     

Dynamics Studies on Molecular Diffusion in Zeolites

1 INTRODUCTION Zeolites have attracted much attention in both scientific and industrial areas for their special characteristics and multiple uses. Zeolites are composed of TO4 (T = Si, Al, Ga, P, etc.) tetrahedra which are connected with each other by sharing oxygen atoms to produce a complex and repetitive three-dimensional atom network with regular molecular dimension cavities joined by channels. Shape selectivity is the most important property of zeolites. Combined with the possib…     

Development and validation of empirical force field parameters for netropsin

The netropsin molecule preferentially binds to the four consecutive A.T base pairs of the DNA minor groove and could therefore inhibit the expression of specific genes. The understanding of its binding on a molecular level is indispensable for computer-aided design of new antitumor agents. This knowledge could be obtained via molecular dynamics (MD) and docking simulations, but in this case appropriate force field parameters for the netropsin molecule should be explicitly defined. Our parametrization was based on the results of quantum chemical calculations. The resulting set of parameters was able to reproduce bond lengths, bond angles, torsional angles of the ab initio minimized geometry within 0.03 A, 3 deg and 5 deg, respectively, and its vibrational frequencies with a relative error of 4.3% for low and 2.8% for high energy modes. To show the accuracy of the developed parameters we calculated an IR spectrum of the netropsin molecule using MD simulation and found it to be in good agreement with the experimental one. Finally, we performed a 10 ns long MD simulation of the netropsin-DNA complex immersed in explicit water. The overall complex conformation remained stable at all times, and its secondary structure was well retained.     

Drag on a nanotube in uniform liquid argon flow

In this work, nonequilibrium molecular dynamics (MD) simulations were performed to investigate uniform liquid argon flow past a carbon nanotube. In the simulation, nanotubes were modeled as rigid cylinders of carbon atoms. Both argon-argon and argon-carbon interactions were calculated based on Lennard-Jones potential. Simulated drag coefficients were compared with (i) published empirical equation which was based on experiments conducted with macroscale cylinders and (ii) finite element (FE) analyses based on Navier-Stokes equation for flow past a circular cylinder using the same dimensionless parameters used in MD simulations. Results show that classical continuum mechanics cannot be used to calculate drag on a nanotube. In slow flows, the drag coefficients on a single-walled nanotube calculated from MD simulations were larger than those from the empirical equation or FE analysis. The difference increased as the flow velocity decreased. For higher velocity flows, slippage on the surface of the nanotube was identified which resulted in lower drag coefficient from MD simulation. This explains why the drag coefficient from MD dropped faster than those from the empirical equation or FE simulation as the flow velocity increased. It was also found that the drag forces are almost equal for single- and double-walled nanotubes with the same outer diameter, implying that inner tubes do not interact with fluid molecules.     

Predictive power of molecular dynamics receptor structures in virtual screening

Molecular dynamics (MD) simulation is a well-established method for understanding protein dynamics. Conformations from unrestrained MD simulations have yet to be assessed for blind virtual screening (VS) by docking. This study presents a critical analysis of the predictive power of MD snapshots to this regard, evaluating two well-characterized systems of varying flexibility in ligand-bound and unbound configurations. Results from such VS predictions are discussed with respect to experimentally determined structures. In all cases, MD simulations provide snapshots that improve VS predictive power over known crystal structures, possibly due to sampling more relevant receptor conformations. Additionally, MD can move conformations previously not amenable to docking into the predictive range.     

Implementation of pi-pi interactions in molecular dynamics simulation

No explicit pi-pi interaction term has been incorporated in the conventional molecular dynamics (MD) simulation programs in spite of its significant role in the folding of biomolecules and the clustering of organic chemicals. In this article, we propose a technique to emphasize the effect of pi-pi interactions using a function of energy and implement it into an MD simulation program. Several trial calculations show that the pi-pi incorporated program gives improved results consistent with experimental data on atom geometry and has no unfavorable interference with the conventional computational framework. This indicates an importance of the explicit consideration of pi-pi interactions in MD simulation.     

Relative solvation free energies calculated using an ab initio QM/MM-based free energy perturbation method: dependence of results on simulation length

Molecular dynamics (MD) simulations in conjunction with thermodynamic perturbation approach was used to calculate relative solvation free energies of five pairs of small molecules, namely; (1) methanol to ethane, (2) acetone to acetamide, (3) phenol to benzene, (4) 1,1,1 trichloroethane to ethane, and (5) phenylalanine to isoleucine. Two studies were performed to evaluate the dependence of the convergence of these calculations on MD simulation length and starting configuration. In the first study, each transformation started from the same well-equilibrated configuration and the simulation length was varied from 230 to 2,540 ps. The results indicated that for transformations involving small structural changes, a simulation length of 860 ps is sufficient to obtain satisfactory convergence. In contrast, transformations involving relatively large structural changes, such as phenylalanine to isoleucine, require a significantly longer simulation length (>2,540 ps) to obtain satisfactory convergence. In the second study, the transformation was completed starting from three different configurations and using in each case 860 ps of MD simulation. The results from this study suggest that performing one long simulation may be better than averaging results from three different simulations using a shorter simulation length and three different starting configurations.     

Comparison of the glass transition temperature and fragility parameter of isomalto-olygomer predicted by molecular dynamics simulations with those measured by differential scanning calorimetry

The purpose of this study is to examine whether molecular dynamics (MD) simulations using a commercially available software for personal computers can estimate the glass transition temperature (Tg) of amorphous systems containing pharmaceutically-relevant excipients. MD simulations were carried out with an amorphous matrix model constructed from isomaltoheptaose, and the Tg estimated from the calculated density versus temperature profile was compared with the Tg measured by differential scanning calorimetry (DSC) for freeze-dried isomalto-oligomer having an average molecular weight close to that of isomaltoheptaose. The Tg values determined by DSC were lower by 10 to 20 K than those extrapolated from the Tg values estimated by MD simulation. Fragility parameter was estimated to be 56 and 51 from MD simulation and from DSC measurement, respectively. Thus, the results suggest that MD simulation can provide approximate estimates for the Tg and fragility parameter of amorphous formulations. However, a reduction of the cooling rate, achievable by sufficiently elongating the simulation duration, is necessary for more accurate estimation.     

Molecular Dynamics Simulation of Glass Transition Behavior of Polyimide Ensemble

The prediction of glass transition temperature from chemical structure has a great significance to select and design new high-properties materials. However, for the estimation and correlation methods, the deficiency of parameters for newer groups will lead to invalidity of Tg prediction or greater deviation from experiment. In the present work, we predicted Tg for a polyimide (PI) ensemble with rigid moieties, and analyzed structural factor that regards to the rotation barrier of the bridging…     

超临界CO2中甲醇和乙醇无限稀释扩散系数的分子动力学模拟与实验测定

采用分子动力学模拟(MD)方法对甲醇和乙醇在超临界二氧化碳中的无限稀释扩散系数进行了模拟计算, 并应用泰勒分散理论, 采用超临界色谱仪对模拟结果进行了实验验证. 模拟计算值与实验值较吻合, 且变化规律基本一致, 表明采用这种新方法可以准确有效地预测超临界体系的扩散性质, 能够方便地应用于工程设计.     

Self-assembly of amphiphilic peptides to construct activatable nanophotosensitizers for theranostic photodynamic therapy

A variety of nano-engineered photosensitizers have been developed for photodynamic therapy (PDT) of cancer diseases. However, traditional nano-engineering methods usually cannot avoid drug leakage and premature release, and have disadvantages such as low drug load and inaccurate release. The self-assembly strategy based on amphiphilic peptides has been considered to be more attractive nano-engineering method. Here we developed novel acid-activatable self-assembled nanophotosensitizers based on an amphiphilic peptide derivative. The peptide derivative was synthesized from a fluorescein molecule with thermally activated delayed fluorescence (TADF). The self-assembled nanophotosensitizers can specifically enter the tumor cells and disassemble inside lysosomes companied with “turn-on” fluorescence and photodynamic therapy effect. Such smart nanophotosensitizers will open new opportunities for cancer theranostics.     

Ab initio protein structure prediction with force field parameters derived from water-phase quantum chemical calculation

Molecular dynamics (MD) simulations are extensively used in the study of the structures and functions of proteins. Ab initio protein structure prediction is one of the most important subjects in computational biology, and many trials have been performed using MD simulation so far. Since the results of MD simulations largely depend on the force field, reliable force field parameters are indispensable for the success of MD simulation. In this work, we have modified atom charges in a standard force field on the basis of water-phase quantum chemical calculations. The modified force field turned out appropriate for ab initio protein structure prediction by the MD simulation with the generalized Born method. Detailed analysis was performed in terms of the conformational stability of amino acid residues, the stability of secondary structure of proteins, and the accuracy for prediction of protein tertiary structure, comparing the modified force field with a standard one. The energy balance between alpha-helix and beta-sheet structures was significantly improved by the modification of charge parameters.     

A generalized Langevin dynamics approach to model solvent dynamics effects on proteins via a solvent-accessible surface. The carboxypeptidase A inhibitor protein as a model

A generalized Langevin dynamics (GLD) scheme is derived for (bio)macromolecules having internal structure, arbitrary shapes and a size larger than solvent molecules (i.e. proteins). The concept of solvent-accessible surface area (SASA) is used to incorporate solvent effects via external forces thereby avoiding its explicit molecular representation. A simulation algorithm is implemented in the GROMOS molecular dynamics (MD) program including random forces and memory effects, while solvation effects enter via derivatives of the surface area. The potato carboxypeptidase inhibitor (PCI), a small protein, is used to numerically test the approach. This molecule has N- and C-terminal tails whose structure and fluctuations are solvent dependent. A 1-ns MD trajectory was analyzed in depth. X-ray and NMR structures are used in conjunction with MD simulations with and without explicit solvent to gauge the quality of the results. All the analyses showed that the GLD simulation approached the results obtained for the MD simulation with explicit simple-point-charge-model water molecules. The SASAs of the polar atoms show a natural exposure towards the solvent direction. A FLS solvent simulation was completed in order to sense memory effects. The approach and results presented here could be of great value for developing alternatives to the use of explicit solvent molecules in the MD simulation of proteins, expanding its use and the time-scale explored. Received: 2 February 2000 / Revised: 12 March 2000 / Accepted: 26 May 2000 / Published online: 2 November 2000     

Enhanced sampling method in molecular simulations using genetic algorithm for biomolecular systems

We propose a molecular simulation method using genetic algorithm (GA) for biomolecular systems to obtain ensemble averages efficiently. In this method, we incorporate the genetic crossover, which is one of the operations of GA, to any simulation method such as conventional molecular dynamics (MD), Monte Carlo, and other simulation methods. The genetic crossover proposes candidate conformations by exchanging parts of conformations of a target molecule between a pair of conformations during the simulation. If the candidate conformations are accepted, the simulation resumes from the accepted ones. While conventional simulations are based on local update of conformations, the genetic crossover introduces global update of conformations. As an example of the present approach, we incorporated genetic crossover to MD simulations. We tested the validity of the method by calculating ensemble averages and the sampling efficiency by using two kinds of peptides, ALA3 and (AAQAA)₃. The results show that for ALA3 system, the distribution probabilities of backbone dihedral angles are in good agreement with those of the conventional MD and replica-exchange MD simulations. In the case of (AAQAA)₃ system, our method showed lower structural correlation of α-helix structures than the other two methods and more flexibility in the backbone ψ angles than the conventional MD simulation. These results suggest that our method gives more efficient conformational sampling than conventional simulation methods based on local update of conformations. © 2018 Wiley Periodicals, Inc.     

Molecular Dynamics Simulations and Steered Molecular Dynamics Simulations of Glabridin Bound to Wild Type and V30A Mutant Transthyretin: Ligand-linked Perturbation of Tertiary Conformation

Transthyretin(TTR), as a tetrameric protein, functions as a neuroprotector. The native TTR homotetramer dissociates into dimers and monomers. Dimers and monomers self-assemble into amyloid fibrils, and this process can lead to some diseases. Native TTR homotetramer is a widely accepted model for TTR amyloid formation. In this study, simulations using molecular dynamics(MD) and steered MD(SMD) were performed to explore the mechanisms for glabridin(Glab), a specific inhibitor for TTR binding, for V30A mutant and wild-type(WT) TTR. MD simulation results indicate that, compared with Glab binding to WT and V30A mutant, the WT TTR could lead to the collapse of β-strands from Ser52 to His56 at chain A. This phenomenon facilitated the easy dissociation of chains A and C. Calculations of the binding free energy between the two chains showed that the V30A-Glab TTR complex displayed a lower binding energy than other systems(WT TTR and WT-Glab TTR). Then, SMD simulation was performed to explore the unbinding pathway for Glab through the WT and V30A mutant TTR. The results show that Lys15(chain A) produced a hydrogen bond with Glab at the force peak via the WT TTR tunnel. Meanwhile, in the V30A TTR mutant, the hydrogen bond between Lys15(chain A) and Glab was broken at the force peak. This condition was beneficial for Glab to be taken off from the protein. Our theoretical results will be useful in designing a new specific inhibitor of TTR protein to control the TTR homotetramer dissociation.