Molecular Dynamics Program Research Articles

Temperature and Stretching Effects on Complementarity Determining Regions (CDRs) Conformation and Stability of Nimotuzumab F(ab)-Fragment

Nimotuzumab is a humanized monoclonal antibody (mAb), a potential anticancer against epidermal growth factor receptor (EGFR)overexpressed by glioma, head and neck, lung, ovarium, and colon cancers. The combination of its use with both external and internal beam radiotherapies showed improvement of the therapeutic effect. However, the high molecular weight slows its uptake on tumor cells. In a recent development, nimotuzumab has been fragmented and then labeled using diagnostic and therapeutic radionuclides, such as gallium-68, yttrium-90, lutetium-177, and holmium-166. In that preparation, nimotuzumab is often conditioned in various environments with variations of pH, temperature and the presence of other compounds. In this research, molecular dynamics (MD) simulation have been carried out to study the CDRs conformational change of nimotuzumab due to the effect of temperature, and also steered molecular dynamics (SMD) simulation to study the stability of nimotuzumab domain as a result of external forces. The simulations were performed using the Not Just Another Molecular Dynamics (NAMD) program package and the analysis was performed with the Visual Molecular Dynamics (VMD) program package. Based on the stability analysis of each residue on the heavy chain, the active site (CDR3 region) that is at residues numbered 98 (Tryptophan) and 99 (Phenylalanine) has the highest conformational changes. On the light chain, the change occurs at residues numbered 1 (Aspartat), 127 (Serin), and 186 (Tyrosine); and that none of that residues is part of active site or CDRs region of the light chain. The SMD simulation was carried out by fixing the N-terminal end of the heavy chain and applying external forces to the C-terminal end. The pulling was set at a constant velocity of 0.5 Å/ps. The force peak arising at the beginning of the unfolding process is 1226 pN. This force was allegedly caused by the rupture of hydrogen bonds between the heavy chain residue VAL211 (Valine) and the heavy chain residue TYR194 (Tyrosine). Received: 04 October 2014; Revised: 13 March 2015; Accepted 23 March 2015

Dynamic force matching: A method for constructing dynamical coarse-grained models with realistic time dependence.

Coarse-grained (CG) models of molecular systems, with fewer mechanical degrees of freedom than an all-atom model, are used extensively in chemical physics. It is generally accepted that a coarse-grained model that accurately describes equilibrium structural properties (as a result of having a well constructed CG potential energy function) does not necessarily exhibit appropriate dynamical behavior when simulated using conservative Hamiltonian dynamics for the CG degrees of freedom on the CG potential energy surface. Attempts to develop accurate CG dynamic models usually focus on replacing Hamiltonian motion by stochastic but Markovian dynamics on that surface, such as Langevin or Brownian dynamics. However, depending on the nature of the system and the extent of the coarse-graining, a Markovian dynamics for the CG degrees of freedom may not be appropriate. In this paper, we consider the problem of constructing dynamic CG models within the context of the Multi-Scale Coarse-graining (MS-CG) method of Voth and coworkers. We propose a method of converting a MS-CG model into a dynamic CG model by adding degrees of freedom to it in the form of a small number of fictitious particles that interact with the CG degrees of freedom in simple ways and that are subject to Langevin forces. The dynamic models are members of a class of nonlinear systems interacting with special heat baths that were studied by Zwanzig [J. Stat. Phys. 9, 215 (1973)]. The properties of the fictitious particles can be inferred from analysis of the dynamics of all-atom simulations of the system of interest. This is analogous to the fact that the MS-CG method generates the CG potential from analysis of equilibrium structures observed in all-atom simulation data. The dynamic models generate a non-Markovian dynamics for the CG degrees of freedom, but they can be easily simulated using standard molecular dynamics programs. We present tests of this method on a series of simple examples that demonstrate that the method provides realistic dynamical CG models that have non-Markovian or close to Markovian behavior that is consistent with the actual dynamical behavior of the all-atom system used to construct the CG model. Both the construction and the simulation of such a dynamic CG model have computational requirements that are similar to those of the corresponding MS-CG model and are good candidates for CG modeling of very large systems.

Parameterization of an interfacial force field for accurate representation of peptide adsorption free energy on high-density polyethylene.

Interfacial force field (IFF) parameters for use with the CHARMM force field have been developed for interactions between peptides and high-density polyethylene (HDPE). Parameterization of the IFF was performed to achieve agreement between experimental and calculated adsorption free energies of small TGTG-X-GTGT host-guest peptides (T = threonine, G = glycine, and X = variable amino-acid residue) on HDPE, with ±0.5 kcal/mol agreement. This IFF parameter set consists of tuned nonbonded parameters (i.e., partial charges and Lennard-Jones parameters) for use with an in-house-modified CHARMM molecular dynamic program that enables the use of an independent set of force field parameters to control molecular behavior at a solid-liquid interface. The R correlation coefficient between the simulated and experimental peptide adsorption free energies increased from 0.00 for the standard CHARMM force field parameters to 0.88 for the tuned IFF parameters. Subsequent studies are planned to apply the tuned IFF parameter set for the simulation of protein adsorption behavior on an HDPE surface for comparison with experimental values of adsorbed protein orientation and conformation.

Modeling, molecular dynamics, and docking assessment of transcription factor rho: a potential drug target in Brucella melitensis 16M.

The zoonotic disease brucellosis, a chronic condition in humans affecting renal and cardiac systems and causing osteoarthritis, is caused by Brucella, a genus of Gram-negative, facultative, intracellular pathogens. The mode of transmission and the virulence of the pathogens are still enigmatic. Transcription regulatory elements, such as rho proteins, play an important role in the termination of transcription and/or the selection of genes in Brucella. Adverse effects of the transcription inhibitors play a key role in the non-successive transcription challenges faced by the pathogens. In the investigation presented here, we computationally predicted the transcription termination factor rho (TtFRho) inhibitors against Brucella melitensis 16M via a structure-based method. In view the unknown nature of its crystal structure, we constructed a robust three-dimensional homology model of TtFRho’s structure by comparative modeling with the crystal structure of the Escherichia coli TtFRho (Protein Data Bank ID: 1PVO) as a template in MODELLER (v 9.10). The modeled structure was optimized by applying a molecular dynamics simulation for 2 ns with the CHARMM (Chemistry at HARvard Macromolecular Mechanics) 27 force field in NAMD (NAnoscale Molecular Dynamics program; v 2.9) and then evaluated by calculating the stereochemical quality of the protein. The flexible docking for the interaction phenomenon of the template consists of ligand-related inhibitor molecules from the ZINC (ZINC Is Not Commercial) database using a structure-based virtual screening strategy against minimized TtFRho. Docking simulations revealed two inhibitors compounds – ZINC24934545 and ZINC72319544 – that showed high binding affinity among 2,829 drug analogs that bind with key active-site residues; these residues are considered for protein-ligand binding and unbinding pathways via steered molecular dynamics simulations. Arg215 in the model plays an important role in the stability of the protein-ligand complex via a hydrogen bonding interaction by aromatic-π contacts, and the ADMET (absorption, distribution, metabolism, and excretion) analysis of best leads indicate nontoxic in nature with good potential for drug development.

Elastic Property of Dynein Motor Domain Obtained from All-Atom Molecular Dynamics Simulations in Explicit Water

Dyneins are large microtubule motor proteins that play important roles in various biological processes. Cytoplasmic dynein is responsible for cell division, cell migration and other basic cellular functions. The motor domain of dynein consists of a ring-shaped ATPase hexamer called the AAA+ modules. Recently, ADP-bound high-resolution structures of cytoplasmic dynein have revealed the organization of the motor domain that comprises the AAA+ ring, the linker, stalk/strut and C-sequence (PDB IDs: 3vkh and 3vkg). However, the high-resolution structure of an ATP-bound dynein remains unclear. Here, we built the ATP model from the ADP model, and carried out a molecular dynamics (MD) simulation of both models to investigate the effect of ATP on the structures and dynamics by comparing their trajectories. The higher resolution structure (3vkg), which is a truncation mutant, was chosen. Then, we modeled the missing residues and added the truncated domain from the wild type structure (3vkh). Four ADP molecules were placed at their original positions in the ADP model. The nucleotide in the AAA1 module, which is important for the dynein's function, was replaced from ADP to ATP in the ATP model. A rectangular water box was placed around dynein. We used our new MD program, psygene-G, which utilizes GPGPU for the acceleration of the non-bonded computation. Electrostatic interactions were treated with our zero-dipole summation method. A 200-ns MD simulation for both models revealed that the stalk of the ATP model was more flexible than that of the ADP model. Additional 100-ns simulations starting from the ADP model with ATP ligand and from the ATP model with ADP ligand reproduced this flexibility. The rigidness of both obtained trajectories qualitatively agrees with experimental results.

Water permeability in carbon nanotube arrays

The membrane composed of carbon nanotube arrays may be widely used in biological molecular devices, image display area and optoelectronic devices. In this paper, the water permeability of the (11, 11) carbon nanotube arrays is simulated by using the SPC/E water model and the molecular dynamics program LAMMPS at 300 K. It is found that the distance between carbon nanotubes has a significant impact on water density distribution and the electric dipole moment orientation. Regardless of the distance between the neighboring tubes, water molecules will get into the nanotubes and form a double-layer cylindrical ring structure inside the nanotubes. However, water molecules can fill into the interstitial space of the nanotube array only when the nearest distance between the neighbor the tubes is greater than 3.4 Å, or the interstitial cross area becomes greater than 57.91 Å2. As the interstitial space increases, the structure of water molecules in the interstitial space will evolve from disconnected single-file chains to boundary-shared close-packing-like columnar circles. Meanwhile, the radius of the water ring inside the nanotube will increase and its boundary becomes more sharp due to the attractions from those water molecules filled in the interstitial space. Relative to the tube axis, the distributions of the water molecular electric dipole moments in the interstitial space depend upon water structures. Under the condition of single-file chain, the distribution exhibits a bimodal characteristic, which is very similar to the distribution of water dipole moments inside the nanotube. Whereas, for the boundary-shared close-packing-like water columnar circle, the distribution of dipole moments shows a unimodal characteristic and the peak corresponds to the angle 90°. This indicates that the preferred orientation of the water dipoles points to the direction perpendicular to the tube axis. These conclusions are helpful in the understanding of the water transport properties in carbon nanotube arrays.

Multiple-Replica Strategies for Free-Energy Calculations in NAMD: Multiple-Walker Adaptive Biasing Force and Walker Selection Rules.

From the most powerful supercomputers to multicore desktops and laptops, parallel computing architectures have been in the mainstream for some time. However, numerical schemes for calculating free energies in molecular systems that directly leverage this hardware paradigm, usually taking the form of multiple-replica strategies, are just now on the cusp of becoming standard practice. Here, we present a modification of the popular molecular dynamics program NAMD that is envisioned to facilitate the use of powerful multiple-replica strategies to improve ergodic sampling for a specific class of free-energy methods known as adaptive biasing force. We describe the software implementation in a so-called multiple-walker context, alongside the interface that makes the proposed approach accessible to the end users. We further evaluate the performance of the adaptive biasing force multiple-walker strategy for a model system, namely, the reversible folding of a short peptide, and show, in particular, in regions of the transition coordinate where convergence of the free-energy calculation is encumbered by hidden barriers, that the multiple-walker strategy can yield far more reliable results in appreciably less real time on parallel architectures, relative to standard, single-replica calculations.

Mapping to Irregular Torus Topologies and Other Techniques for Petascale Biomolecular Simulation.

Currently deployed petascale supercomputers typically use toroidal network topologies in three or more dimensions. While these networks perform well for topology-agnostic codes on a few thousand nodes, leadership machines with 20,000 nodes require topology awareness to avoid network contention for communication-intensive codes. Topology adaptation is complicated by irregular node allocation shapes and holes due to dedicated input/output nodes or hardware failure. In the context of the popular molecular dynamics program NAMD, we present methods for mapping a periodic 3-D grid of fixed-size spatial decomposition domains to 3-D Cray Gemini and 5-D IBM Blue Gene/Q toroidal networks to enable hundred-million atom full machine simulations, and to similarly partition node allocations into compact domains for smaller simulations using multiple-copy algorithms. Additional enabling techniques are discussed and performance is reported for NCSA Blue Waters, ORNL Titan, ANL Mira, TACC Stampede, and NERSC Edison.

Simulation and experimental study of rheological properties of CeO2–water nanofluid

Metal oxide nanoparticles offer great merits over controlling rheological, thermal, chemical and physical properties of solutions. The effectiveness of a nanoparticle to modify the properties of a fluid depends on its diffusive properties with respect to the fluid. In this study, rheological properties of aqueous fluids (i.e. water) were enhanced with the addition of CeO2 nanoparticles. This study was characterized by the outcomes of simulation and experimental results of nanofluids. The movement of nanoparticles in the fluidic media was simulated by a large-scale molecular thermal dynamic program (i.e. LAMMPS). The COMPASS force field was employed with smoothed particle hydrodynamic potential (SPH) and discrete particle dynamics potential (DPD). However, this study develops the understanding of how the rheological properties are affected due to the addition of nanoparticles in a fluid and the way DPD and SPH can be used for accurately estimating the rheological properties with Brownian effect. The rheological results of the simulation were confirmed by the convergence of the stress autocorrelation function, whereas experimental properties were measured using a rheometer. These rheological values of simulation were obtained and agreed within 5 % of the experimental values; they were identified and treated with a number of iterations and experimental tests. The results of the experiment and simulation show that 10 % CeO2 nanoparticles dispersion in water has a viscosity of 2.0–3.3 mPas.

분자동역학과 확률회전동역학을 결합한 멀티스케일 모델링 기법 개발

Multiscale modeling is a new simulation approach which can manage different spatial and temporal scales of system. In this study, as part of multiscale modeling research, we propose the way of combining two different simulation methods, molecular dynamics(MD) and stochastic rotation dynamics(SRD). Our conceptual implementations are based on LAMMPS, one of the well-known molecular dynamics programs. Our prototype of multiscale modeling follows the form of the third party implementation of LAMMPS. It added MD to SRD in order to simulate the boundary area of the simulation box. Because it is important to guarantee the seamless simulation, we also designed the overlap zones and communication zones. The preliminary experimental results showed that our proposed scheme is properly worked out and the execution time is also reduced.

Molecular Dynamics for Two-Body Potential from Unobserved Gaussian Regression

A molecular dynamic simulation requires the local potential energy per atom because it provides the force applied to each atom. On the other hand, an electronic structure computation provides only the global potential energy of an atomic system. We propose a stochastic fitting for deducing a potential from a total energy which can be incorporated inside a molecular dynamic program. The objective of that fitting process is twofold. First, the total energy can be reproduced with a sufficient accuracy. In addition, we want to separate the potential energy into atomic contributions. The only inputs in the stochastic regression are the total energies of the atomic systems. As for the applications, we examine the performance of the method with the help of a mathematical model. Afterward, we use it for quantum applications in which we compare the direct method and the unobserved fitting with respect to the energy conservations. For a molecular dynamic application, we examine the atomic cluster formations during freezing when the proposed potential is used. Although the method is generally applicable, we restrict in this paper to total energies which are reproduced from two-body potentials for the molecular dynamic simulation.

ST‐analyzer: A web‐based user interface for simulation trajectory analysis

Molecular dynamics (MD) simulation has become one of the key tools to obtain deeper insights into biological systems using various levels of descriptions such as all-atom, united-atom, and coarse-grained models. Recent advances in computing resources and MD programs have significantly accelerated the simulation time and thus increased the amount of trajectory data. Although many laboratories routinely perform MD simulations, analyzing MD trajectories is still time consuming and often a difficult task. ST-analyzer, http://im.bioinformatics.ku.edu/st-analyzer, is a standalone graphical user interface (GUI) toolset to perform various trajectory analyses. ST-analyzer has several outstanding features compared to other existing analysis tools: (i) handling various formats of trajectory files from MD programs, such as CHARMM, NAMD, GROMACS, and Amber, (ii) intuitive web-based GUI environment--minimizing administrative load and reducing burdens on the user from adapting new software environments, (iii) platform independent design--working with any existing operating system, (iv) easy integration into job queuing systems--providing options of batch processing either on the cluster or in an interactive mode, and (v) providing independence between foreground GUI and background modules--making it easier to add personal modules or to recycle/integrate pre-existing scripts utilizing other analysis tools. The current ST-analyzer contains nine main analysis modules that together contain 18 options, including density profile, lipid deuterium order parameters, surface area per lipid, and membrane hydrophobic thickness. This article introduces ST-analyzer with its design, implementation, and features, and also illustrates practical analysis of lipid bilayer simulations.

New Thermal Neutron Scattering Kernels for Light and Heavy Water Based on Molecular Dynamics Simulations

Calculations of moderators require scattering kernels that are accurate in both the energetics and angular distribution of outgo- ing neutrons. Currently, scattering cross sections available in ENDF format to be used in Monte Carlo and deterministic calculations rely on water models that do not utilize the up-to-date knowledge of its structure and dynamics.In this work we present a new model to compute the scattering kernels for light and heavy water based on molecular dynamics simulations. Using the molecular dynamics program GROMACS and a flexible TIP4P model we obtained the frequency spectra of hydrogen, deuterium and oxygen, bound in light and heavy water. With those spectra we computed the scattering laws using the LEAPR module of NJOY, which uses the incoherent approximation. Scattering laws for D and O in D2O are corrected using the Skld approximation and partial structure factors obtained by Soper.Using those kernels we computed double differential and integral cross sections over a wide range of neutron energies (10−5 1eV). These results represent an improvement over existing models when compared with experimental values, especially for low incident neutron energies.

A MD Study on the Temperature Influence on Ni/Al Interface at Initial Diffusion Time

The molecular dynamic method and interface diffusion theory are used to simulate Ni/Al metal interface diffusion. One of the unit cells containing 576 Ni atoms and 128 Al atoms is chosen and computed under different temperatures (600K, 700K, 800K, 900K, 1000K, 1100K, 1200K, 1300K), respectively. We mainly analyze the position image of the interface diffusion atoms of Ni/Al interface reaction and the radial distribution function curve of the selected region, after the molecular dynamics program running 1200000 steps, under different temperatures, at initial diffusion time.

MDSLB: A new static load balancing method for parallel molecular dynamics simulations

Large-scale parallelization of molecular dynamics simulations is facing challenges which seriously affect the simulation efficiency, among which the load imbalance problem is the most critical. In this paper, we propose, a new molecular dynamics static load balancing method (MDSLB). By analyzing the characteristics of the short-range force of molecular dynamics programs running in parallel, we divide the short-range force into three kinds of force models, and then package the computations of each force model into many tiny computational units called “cell loads”, which provide the basic data structures for our load balancing method. In MDSLB, the spatial region is separated into sub-regions called “local domains”, and the cell loads of each local domain are allocated to every processor in turn. Compared with the dynamic load balancing method, MDSLB can guarantee load balance by executing the algorithm only once at program startup without migrating the loads dynamically. We implement MDSLB in OpenFOAM software and test it on TianHe-1A supercomputer with 16 to 512 processors. Experimental results show that MDSLB can save 34%–64% time for the load imbalanced cases.

Molecular Dynamics Simulations Accelerated by GPU for Biological Macromolecules with a Non-Ewald Scheme for Electrostatic Interactions.

A molecular dynamics (MD) simulation program for biological macromolecules was implemented with a non-Ewald scheme for long-ranged electrostatic interactions and run on a general purpose graphics processing unit (GPU). We recently developed several non-Ewald methods to compute the electrostatic energies with high precision. In particular, the zero-dipole summation (ZD) method, which takes into account the neutralities of charges and dipoles in a truncated subset, enables the calculation of electrostatic interactions with high accuracy and low computational cost, and its algorithm is simple enough to be implemented in a GPU. We developed an MD program with the space decomposition algorithm, myPresto/psygene, and applied it to several biological macromolecular systems with GPUs implementing the ZD method. Rapid computing performance with high accuracy was obtained.

The PYXAID Program for Non-Adiabatic Molecular Dynamics in Condensed Matter Systems.

This work introduces the PYXAID program, developed for non-adiabatic molecular dynamics simulations in condensed matter systems. By applying the classical path approximation to the fewest switches surface hopping approach, we have developed an efficient computational tool that can be applied to study photoinduced dynamics at the ab initio level in systems composed of hundreds of atoms and involving thousands of electronic states. The technique is used to study in detail the ultrafast relaxation of hot electrons in crystalline pentacene. The simulated relaxation occurs on a 500 fs time scale, in excellent agreement with experiment, and is driven by molecular lattice vibrations in the 200-250 cm(-1) frequency range. The PYXAID program is organized as a Python extension module and can be easily combined with other Python-driven modules, enhancing user-friendliness and flexibility of the software. The source code and additional information are available on the Web at the address http://gdriv.es/pyxaid . The program is released under the GNU General Public License.

Model structure of a full-length anti-IgE complexed with IgE (P3384)

Abstract Modeling antibody/antigen (Ab/Ag) complexes remains a challenging problem and is important for understanding how proteins associate, which in turn can aid drug design. Recently, we have implemented a method (EMAP) for producing the conformations of Ab/Ag complexes in the widely used molecular dynamics program CHARMM. Here, we apply this method to model the structure of IgE in complex with omalizumab, a humanized IgG1 antibody that has been approved in many countries for treating severe, persistent allergic asthma. First, the EMAP method was calibrated by using it to reproduce 24 nonredundant Ab/Ag complexes whose bound and unbound structures have been solved. It could yield near-native conformations for 22 of the 24 complexes, whereas other docking methods such as ZDOCK yield less near-native conformations. Having validated the EMAP method, it was used to dock full-length models of omalizumab and IgE together. The resulting IgE/omalizumab complex structure provides insights into the relative importance of the residues involved in binding. It also provides a plausible explanation for why omalizumab and IgE do not form large immune complexes.

A Minimal Implementation of the AMBER-PAICS Interface for Ab Initio FMO-QM/MM-MD Simulation

Abstract For the purpose of providing a realistic description of the reaction mechanisms in large molecular systems, we propose a quantum mechanical/molecular mechanical (QM/MM) method combined with the ab initio fragment molecular orbital (FMO) method, i.e., the ab initio FMO-QM/MM method. By connecting a molecular dynamics (MD) program AMBER with an FMO program PAICS, we have implemented an AMBER-PAICS interface (AP-IF). Using the AP-IF, we demonstrate three example applications: (a) a hydrogen fluoride and water molecular clusters, (b) an alanine dipeptide in aqueous solution, and (c) a prion protein–GN8 complex. From these results, it is confirmed that the FMO-QM/MM method offers a good compromise between chemical accuracy and computational cost and enables us to obtain in ab initio quality the inter- and intramolecular interaction energies between molecules or residues in large molecular systems such as solution and biomolecule, by using the dynamics-based interfragment interaction energy (IFIE) analysis.

A simplified confinement method for calculating absolute free energies and free energy and entropy differences.

A simple and robust formulation of the path-independent confinement method for the calculation of free energies is presented. The simplified confinement method (SCM) does not require matrix diagonalization or switching off the molecular force field, and has a simple convergence criterion. The method can be readily implemented in molecular dynamics programs with minimal or no code modifications. Because the confinement method is a special case of thermodynamic integration, it is trivially parallel over the integration variable. The accuracy of the method is demonstrated using a model diatomic molecule, for which exact results can be computed analytically. The method is then applied to the alanine dipeptide in vacuum, and to the α-helix ↔ β-sheet transition in a 16-residue peptide modeled in implicit solvent. The SCM requires less effort for the calculation of free energy differences than previous formulations because it does not require computing normal modes. The SCM has a diminished advantage for determining absolute free energy values, because it requires decreasing the MD integration step to obtain accurate results. An approximate confinement procedure is introduced, which can be used to estimate directly the configurational entropy difference between two macrostates, without the need for additional computation of the difference in the free energy or enthalpy. The approximation has convergence properties similar to those of the standard confinement method for the calculation of free energies. The use of the approximation requires about 5 times less wall-clock simulation time than that needed to compute enthalpy differences to similar precision from an MD trajectory. For the biomolecular systems considered in this study, the errors in the entropy approximation are under 10%. Practical applications of the methods to proteins are currently limited to implicit solvent simulations.