Chemistry At HARvard Molecular Mechanics Research Articles

Prediction of binding characteristics between von Willebrand factor and platelet glycoprotein Ibα with various mutations by molecular dynamic simulation

IntroductionBinding of platelet glycoprotein (GP)Ibα with von-Willebrand factor (VWF) exclusively mediates the initial platelet adhesion to injured vessel wall. To understand the mechanism of biomedical functions, we calculated the dynamic fluctuating three-dimensional (3D) structures and dissociation energy for GPIbα with various single amino-acid substitution at G233, which location is known to cause significant changes in platelet adhesive characteristics. Material and methodsMolecular dynamics (MD) simulation was utilized to calculate 3D structures and Potential of Mean Force (PMF) for wild-type VWF bound with wild-type, G233A (equal function), G233V (gain of function), and G233D (loss of function) GPIbα. Simulation was done on water-soluble condition with time-step of 2 × 10−15 s using NAnoscale Molecular Dynamics (NAMD) with Chemistry at HARvard Molecular Mechanics (CHARMM) force field. Initial structure for each mutant was obtained by inducing single amino-acid substitution to the stable water-soluble binding structure of wild-type. ResultsThe most stable structures of wild-type VWF bound to GPIbα in wild-type or any mutant did not differ. However, bond dissociation energy defined as difference of PMF between most stable structure and the structure at 65 Å mass center distances in G233D was 4.32 kcal/mol (19.5%) lower than that of wild-type. Approximately, 2.07 kcal/mol energy was required to dissociate VWF from GPIbα with G233V at mass center distance from 48 to 52 Å, which may explain the apparent “gain of function” in G233V. ConclusionThe mechanism of substantially different biochemical characteristics of GPIbα with mutations in G233 location was predicted from physical movement of atoms constructing these proteins.

Abstract 770: Potential Explanation of the Mechanism for Loss of Function with G233D Mutation in Platelet Glycoprotein Ibα: Results fromMolecular Dynamics Simulation

Background: Platelet play crucial role for the onset of acute coronary syndrome. The initial binding following vessel injury is exclusively mediated by the binding of von Willebrand factor (VWF) and platelet glycoprotein (GP) Ib α . Previous biological experiments revealed loss of function of platelet expressing GPIb α with G233D mutation. Objective: To elucidate the mechanism underlining the loss of function in G233D mutant. Methods: Dynamic fluctuating three-dimensional structures and the Potential of Mean Force (PMF) were calculated for the binding of VWF and platelet GPIb α in wild-type or G233D mutant. PMF were calculated at each 0.5Å for 25 Å to 65 Å of mass center distance between GPIb α and VWF. The energy required to dissociate the bond between GPIb α and VWF was calculated by subtracting the lowest PMF from the PMF at 65 Å mass center distance. Chemistry at HARvard Molecular Mechanics (CHARMM) force field with NAnoscale Molecular Dynamics (NAMD) was used for calculation. The initial structure of each mutant was obtained by inducing single amino-acid substitution with Visual Molecular Dynamics (VMD) to the stable water-soluble binding structure of wild-type VWF and GPIb α . Results: The energetically most stable binding structure of VWF and GPIb α in wild-type and G233D did not differ substantially (Figure panel A). However, The energy required to dissociate the bond between GPIb α and VWF was 4.32 kcal/mol (19.5 %) lower for G233D mutant compared to wild-type (Figure panel B). Conclusions: Our results suggest that the reduction of dissociation energy of single molecule of G233D GPIb α mutant as a possible explanation for the reduced platelet adhesion under blood flow condition.

The CHARMM-TURBOMOLE interface for efficient and accurate QM/MM molecular dynamics, free energies, and excited state properties.

The quantum mechanical (QM)/molecular mechanical (MM) interface between Chemistry at HARvard Molecular Mechanics (CHARMM) and TURBOMOLE is described. CHARMM provides an extensive set of simulation algorithms, like molecular dynamics (MD) and free energy perturbation, and support for mature nonpolarizable and Drude polarizable force fields. TURBOMOLE provides fast QM calculations using density functional theory or wave function methods and excited state properties. CHARMM-TURBOMOLE is well-suited for extended QM/MM MD simulations using first principles methods with large (triple-ζ) basis sets. We demonstrate these capabilities with a QM/MM simulation of Mg(2+) (aq), where the MM outer sphere water molecules are represented using the SWM4-NDP Drude polarizable force field and the ion and inner coordination sphere are represented using QM PBE, PBE0, and MP2 methods. The relative solvation free energies of Mg(2+) and Zn(2+) were calculated using thermodynamic integration. We also demonstrate the features for excited state properties. We calculate the time-averaged solution absorption spectrum of indole, the emission spectrum of the indole 1La excited state, and the electronic circular dichroism spectrum of an oxacepham.

The liquid surface of chiral ionic liquids as seen from molecular dynamics simulations combined with intrinsic analysis

We present molecular-level insight into the liquid/gas interface of two chiral room-temperature ionic liquids (RTILs) derived from 1-n-butyl-3-methylimidazolium bromide ([bmim][Br]); namely, (R)-1-butyl-3-(3-hydroxy-2-methylpropyl)imidazolium bromide (hydroxypropyl) and 1-butyl-3-[(1R)-nopyl]imidazolium bromide (nopyl). We use our currently developed force field which was validated against the experimental bulk density, heat of vaporization, and surface tension of [bmim][Br]. The force field for the RTILs adopts the Chemistry at Harvard Molecular Mechanics (CHARMM) parameters for the intramolecular and repulsion-dispersion interactions along with the reduced partial atomic charges based on ab initio calculations. The net charges of the ions are around ±0.8e, which mimic the anion to cation charge transfer and many-body effects. Molecular dynamics simulations in the slab geometry combined with the intrinsic interface analysis are employed to provide a detailed description of the RTIL/gas interface in terms of the structural and dynamic properties of the interfacial, sub-interfacial, and central layers at a temperature of 300 K. The focus is on the comparison of the liquid/gas interface for the chiral RTILs with the interface for parent [bmim][Br]. The structure of the interface is elucidated by evaluating the surface roughness, intrinsic atomic density profiles, and orientation ordering of the cations. The dynamics of the ions at the interfacial region is characterized by computing the survival probability, and normal and lateral self-diffusion coefficients in the layers.

QuanPol: A full spectrum and seamless QM/MM program

The quantum chemistry polarizable force field program (QuanPol) is implemented to perform combined quantum mechanical and molecular mechanical (QM/MM) calculations with induced dipole polarizable force fields and induced surface charge continuum solvation models. The QM methods include Hartree-Fock method, density functional theory method (DFT), generalized valence bond theory method, multiconfiguration self-consistent field method, Møller-Plesset perturbation theory method, and time-dependent DFT method. The induced dipoles of the MM atoms and the induced surface charges of the continuum solvation model are self-consistently and variationally determined together with the QM wavefunction. The MM force field methods can be user specified, or a standard force field such as MMFF94, Chemistry at Harvard Molecular Mechanics (CHARMM), Assisted Model Building with Energy Refinement (AMBER), and Optimized Potentials for Liquid Simulations-All Atom (OPLS-AA). Analytic gradients for all of these methods are implemented so geometry optimization and molecular dynamics (MD) simulation can be performed. MD free energy perturbation and umbrella sampling methods are also implemented.

Parametrization of Ligands Associated with the RNA Dependent RNA Polymerase Found in Hepatitis C Virus

Hepatitis C virus (HCV) is a wide spread health concern and affects approximately 35,000 new cases in the U.S. each year. Though there are treatments available, they cause many unpleasant side effects and are not completely effective. HCV contains a positive sense single-stranded RNA genome and replicates with the aid of RNA Dependent RNA polymerase (RdRp). Certain naturally occurring ligands have been found to exhibit allosteric properties towards RdRp. These inhibitors are termed “allosteric” because they bind to the enzyme at locations other than the activation site.Our goal is to discover the properties of such ligands that bond to the enzyme in this manner. We will computationally model these chemicals and compare them to others that may demonstrate the same traits in order to take a multi-faceted approach to allosterically inhibit RdRp.By utilizing programs such as CHARMM (Chemistry at HARvard Molecular Mechanics) and Gaussian, as well as molecular visualization programs, we will model and view the ligands to further understand the properties that make them unique.The information obtained from our computational modeling of the ligands will be compiled and processed with the information obtained from the protein they bind to and combined together to determine the nature of their interaction.

Molecular dynamics simulations of matrix assisted laser desorption ionization: Matrix–analyte interactions

There is synergy between matrix assisted laser desorption ionization (MALDI) experiments and molecular dynamics (MD) simulations. To understand analyte ejection from the matrix, MD simulations have been employed. Prior calculations show that the ejected analyte molecules remain solvated by the matrix molecules in the ablated plume. In contrast, the experimental data show free analyte ions. The main idea of this work is that analyte molecule ejection may depend on the microscopic details of analyte interaction with the matrix. Intermolecular matrix–analyte interactions have been studied by focusing on 2,5-dihydroxybenzoic acid (DHB; matrix) and amino acids (AA; analyte) using Chemistry at HARvard Molecular Mechanics (CHARMM) force field. A series of AA molecules have been studied to analyze the DHB–AA interaction. A relative scale of AA molecule affinity towards DHB has been developed.

CHARMM: the biomolecular simulation program.

CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983.

Comparison of the Extended Isotropic Periodic Sum and Particle Mesh Ewald Methods for Simulations of Lipid Bilayers and Monolayers

3D-IPS/DFFT is an extension of the three-dimensional isotropic periodic sum (3D-IPS) for evaluation of electrostatic and Lennard-Jones interactions in heterogeneous systems; it utilizes a discrete fast Fourier transform (DFFT) for efficient calculation of the IPS potential with a large local region radius. The method is demonstrated to be highly accurate for simple bulk fluids, liquid/liquid and liquid/vapor interfaces, and lipid bilayers and monolayers. Values for r(C) (the cutoff distance for direct evaluation of pairs) and R(C) (the local region radius) equal to 10 A and twice the longest edge of the periodic cell, respectively, provide excellent efficiency and accuracy. Dimyristoylphosphatidylcholine (DMPC) monolayers simulated with the CHARMM (Chemistry at HARvard Molecular Mechanics) C27r lipid parameter set and 3D-IPS/DFFT yield surface tensions approximately 8 dyn/cm higher than those simulated using particle mesh Ewald (PME), and with experiment. In contrast, surface tensions for DMPC bilayers are 16 dyn/cm/leaflet with both 3D-IPS/DFFT (r(C) = 10 and 12 A) and PME (r(C) = 12 A). This indicates that PME (r(C) = 12 A) may be used for simulations of bilayers, but not monolayers, and that the large bilayer surface tension arising from C27r is incorrect.

Molecular Dynamics Simulations of a DMPC Bilayer Using Nonadditive Interaction Models

We present a polarizable force field based on the charge-equilibration formalism for molecular dynamics simulations of phospholipid bilayers. We discuss refinement of headgroup dihedral potential parameters to reproduce ab initio conformational energies of dimethylphosphate calculated at the MP2/cc-pVTZ level of theory. We also address the refinement of electrostatic and Lennard-Jones (van der Waals) parameters to reproduce ab initio polarizabilities and water interaction energies of dimethylphosphate and tetramethylammonium. We present results of molecular dynamics simulations of a solvated dimyristoylphosphatidylcholine bilayer using this polarizable force field as well as the nonpolarizable, fixed-charge CHARMM27 and CHARMM27r force fields for comparison. Calculated atomic and electron-density profiles, deuterium order parameters, and headgroup orientations are found to be consistent with previous simulations and with experiment. Polarizable interaction models for solvent and lipid exhibit greater water penetration into the lipid interior; this is due to the variation of water molecular dipole moment from a bulk value of 2.6 Debye to a value of 1.9 Debye in the membrane interior. The reduction in the electrostatic component of the desolvation free-energy penalty allows for greater water density. The surface dipole potential predicted by the polarizable model is 0.95 V compared to the value of 0.8 V based on nonpolarizable force-field calculations. Effects of inclusion of explicit polarization are discussed in relation to water dipole moment and varying charge distributions. Dielectric permittivity profiles for polarizable and nonpolarizable interactions exhibit subtle differences arising from the nature of the individual component parameterizations; for the polarizable force field, we obtain a bulk dielectric permittivity of 79, whereas the nonpolarizable force field plateaus at 97 (the value for pure TIP3P water). In the membrane interior, both models predict unit permittivities, with the polarizable models contributing from one to two more units due to the optical dielectric (high-frequency dipole fluctuations). This contribution is a step toward the continuing development of a CHARMM (Chemistry at Harvard Molecular Mechanics) polarizable force field for simulations of biomacromolecular systems.

Revised Charge Equilibration Potential for Liquid Alkanes

We present a revised liquid alkane force field based on the charge equilibration formalism for incorporating electrostatic nonadditive effects arising from local polarization. The model is a revision of earlier work by Patel and Brooks, specifically addressing deficiencies in the dihedral potential, electrostatic, and Lennard-Jones (van der Waals) parameters of the force field. We discuss refinement of the alkane backbone torsion potential to match high-level ab initio relative conformational energetics for pentane, hexane, and heptane. We further discuss refinement of the electrostatic and Lennard-Jones (van der Waals) parameters to reproduce the experimental polarizability, liquid density, and vaporization enthalpy of hexane. Finally, we calculate bulk liquid properties including densities, vaporization enthalpies, self-diffusion constants, isothermal compressibilities, constant pressure heat capacities, and NMR T 1 relaxation times for a series of linear alkanes ranging from hexane to pentadecane based on the current revised model. We also compute free energies of hydration for pentane, hexane, and heptane. The revised force field offers a significantly improved overall description of these properties relative to the original parametrization. The current alkane force field represents a platform for ongoing development of a CHARMM (Chemistry at Harvard Molecular Mechanics) polarizable force field for lipids and integral membrane proteins.

The variational explicit polarization potential and analytical first derivative of energy: Towards a next generation force field

A previous article proposed an electronic structure-based polarizable potential, called the explicit polarization (X-POL) potential, to treat many-body polarization and charge delocalization effects in polypeptides. Here, we present a variational version of the X-POL potential, in which the wave function of the entire molecular system is variationally optimized to yield the minimum total electronic energy. This allows the calculation of analytic gradients, a necessity for efficient molecular dynamics simulations. In this paper, the detailed derivations of the Fock matrix and analytic force are presented and discussed. The calculations involve a double self-consistent-field procedure in which the wave function of each fragment is self-consistently optimized in the presence of other fragments, and in addition the polarization of the entire system is self-consistently optimized. The variational X-POL potential has been implemented in the Chemistry at Harvard Molecular Mechanics (CHARMM) package and tested successfully for small model compounds.

Atomistic model of DNA: Phonons and base-pair opening

A fully atomistic model of B-DNA using the CHARMM (chemistry at Harvard molecular mechanics) force field is presented. Molecular dynamics simulations were used to prepare an equilibrium structure. The Hessian of interatomic forces obtained from CHARMM for the equilibrium structure was used as input to a large scale phonon calculation. The calculated dispersion relations at low frequency are compared with recently published experimental data, which shows the model to have good accuracy for the low frequency, vibrational modes of DNA. These are discussed in the context of base-pair opening. In addition to the widely reported modes at, or below, approximately 12.5 meV, a continuous band of modes with strong base-pair opening character is found up to 40 meV, which coincides with the typical denaturation temperature of DNA.

Revisiting the hexane-water interface via molecular dynamics simulations using nonadditive alkane-water potentials

We present results addressing properties of a polarizable force field for hexane based on the fluctuating charge (FQ) formalism and developed in conjunction with the Chemistry at Harvard Molecular Mechanics (CHARMM) potential function. Properties of bulk neat hexane, its liquid-vapor interface, and its interface with a polarizable water model (TIP4P-FQ) are discussed. The FQ model is compared to a recently modified alkane model, C27r, also based on the CHARMM potential energy function. With respect to bulk properties, both models predict bulk density within 1%; the FQ model predicts the liquid vaporization enthalpy within 2%, while the C27r force field underestimates the property by roughly 20% (and in this sense reflects the quality of the C27r force field across the spectrum of linear and branched alkanes). The FQ hexane model realistically captures the dielectric properties of the bulk in terms of a dielectric constant of 1.94, in excellent agreement with experimental values in the range of 1.9-2.02. This behavior is also in conformity with a recent polarizable alkane model based on Drude oscillators. Furthermore, the bulk dielectric is essentially captured in the infinite frequency, or optical, dielectric contribution. The FQ model is in this respect a more realistic force field for modeling lipid bilayer interiors for which most current state-of-the-art force fields do not accurately capture the dielectric environment. The molecular polarizability of the FQ model is 11.79 A3, in good agreement with the range of experimental and ab initio values. In contrast to FQ models of polar solvents such as alcohols and water, there was no need to scale gas-phase polarizabilities in order to avoid polarization catastrophes in the pure bulk. In terms of the liquid-vapor and liquid-liquid interfaces, the FQ model displays a rich orientational structure of alkane and water in the respective interfacial systems, in general conforming with earlier simulation studies of such interfaces. The FQ force field shows a marked deviation in the interfacial dipole potentials computed from the charge densities averaged over simulation trajectories. At the liquid-vapor interface, the FQ model predicts a potential drop of -178.71 mV in contrast to the C27r estimate of -433.80 mV. For the hexane-water interface, the FQ force field predicts a dipole potential drop of -379.40 mV in contrast to the C27r value of -105.42 mV. Although the surface dipole potential predicted by the FQ model is roughly 3.5 times that predicted by the C27r potential, it is consistent with reported experimental potentials across solvated lipid bilayers in the range of 400-600 mV.

A nonadditive methanol force field: Bulk liquid and liquid-vapor interfacial properties via molecular dynamics simulations using a fluctuating charge model

We study the bulk and interfacial properties of methanol via molecular dynamics simulations using a CHARMM (Chemistry at HARvard Molecular Mechanics) fluctuating charge force field. We discuss the parametrization of the electrostatic model as part of the ongoing CHARMM development for polarizable protein force fields. The bulk liquid properties are in agreement with available experimental data and competitive with existing fixed-charge and polarizable force fields. The liquid density and vaporization enthalpy are determined to be 0.809 g/cm3 and 8.9 kcal/mol compared to the experimental values of 0.787 g/cm3 and 8.94 kcal/mol, respectively. The liquid structure as indicated by radial distribution functions is in keeping with the most recent neutron diffraction results; the force field shows a slightly more ordered liquid, necessarily arising from the enhanced condensed phase electrostatics (as evidenced by an induced liquid phase dipole moment of 0.7 D), although the average coordination with two neighboring molecules is consistent with the experimental diffraction study as well as with recent density functional molecular dynamics calculations. The predicted surface tension of 19.66+/-1.03 dyn/cm is slightly lower than the experimental value of 22.6 dyn/cm, but still competitive with classical force fields. The interface demonstrates the preferential molecular orientation of molecules as observed via nonlinear optical spectroscopic methods. Finally, via canonical molecular dynamics simulations, we assess the model's ability to reproduce the vapor-liquid equilibrium from 298 to 423 K, the simulation data then used to obtain estimates of the model's critical temperature and density. The model predicts a critical temperature of 470.1 K and critical density of 0.312 g/cm3 compared to the experimental values of 512.65 K and 0.279 g/cm3, respectively. The model underestimates the critical temperature by 8% and overestimates the critical density by 10%, and in this sense is roughly equivalent to the underlying fixed-charge CHARMM22 force field.

Single-Walled Carbon Nanotubes Acting as ControllableTransport Channels

The motion and equilibrium distribution of water molecules adsorbedinside neutral and negatively charged single-walled carbon nanotubes(SWNTs) have been studied using molecular dynamics simulations (MDSs)at room temperature based on CHARMM (Chemistry at HARvard MolecularMechanics) potential parameters. We find that water molecules have aconspicuous electropism phenomenon and regular tubule patterns insideand outside the charged tube wall. The analyses of the motion behaviourof water molecules in the radial and axial directions show that bycharging the SWNT, the adsorption efficiency is greatly enhanced, andthe electric field produced by the charged SWNTs prevents watermolecules from flowing out of the nanotube. However, water moleculescan travel through the neutral SWNT in a fluctuating manner. Thisindicates that by electrically charging and uncharging the SWNTs, onecan control the adsorption and transport behaviour of polar moleculesin SWNTs for using as a stable storage medium or long transportchannels. The transport velocity can be tailored by changing the chargeon the SWNTs, which may have a further application as modulatabletransport channels.

Large Scale Simulation of Protein Mechanics and Function

The chapter illustrates the state of art in large-scale biomolecular modeling. Such modeling has become feasible only through parallel computing utilizing hundreds and soon thousands of processors. Fortunately, the necessary computers are available to many researchers and the needed new generation of molecular dynamics and molecular visualization programs has been developed and these resources are widely shared. Harnessing them effectively requires great effort, to which purpose the authors' group has developed the molecular dynamics program Not (just) Another Molecular Dynamics program (NAMD). For the graphical analysis of the ensuing gigabytes and terabytes of data the group has developed the program Visual Molecular Dynamics (VMD). These programs are widely used today since the increasing availability of protein structures has led to most biomedical researchers using structural information for the design and analysis of their experiments. The chapter describes NAMD and VMD and illustrates three exemplary simulations of large-scale systems that are presently the subject of intense research. The functions of all three proteins investigated are mainly mechanical. NAMD is primarily designed to work with Chemistry at HARvard Molecular Mechanics (CHARMM) force field parameters. Input files for NAMD can be generated using CHARMM, X-PLOR, or VMD. NAMD has also been extended to read Assisted Model Building with Energy Refinement (AMBER) and GROningen MAchine for Chemical Simulations (GROMACS) input file formats. NAMD running on 768 processors has enabled a record-breaking two million atom 5 ns simulation of the ribosome using an AMBER force field. To relate the observed mechanics to the architecture of proteins is the domain of so-called steered molecular dynamics simulations, contributing to the founding of the new field of mechanobiology, which studies the role of forces in cellular processes.

MMC and LD simulations of alpha-D-Glcp-(1-->2)-alpha-D-Glcp-(1-->3)-alpha-D-Glcp-OMe. A model for the terminal trisaccharide in glycoprotein precursors.

The conformational flexibility and the dynamics of alpha-D-Glcp-(1-->2)-alpha-D-Glcp(1-->3)-alpha-D-Glcp-OMe (I) has been investigated by Metropolis-Monte Carlo with the HSEA (Hard Sphere Exo-Anomeric) force field and Langevin dynamics simulations employing two different CHARMm (Chemistry at HARvard Molecular Mechanics) force fields, CHEAT95 and PARM22. The conformational space spanned by the molecule is similar for the two former force fields but differ significantly for the latter. Hydrogen bonding between O2" and O4 of the title compound is analysed in comparison to NMR and preliminary results from X-ray powder diffraction studies.