In Silico Modeling of Changes to Ventricular Myocyte Action Potential Morphology Caused by Pharmacological Agents (original) (raw)
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Rationalising the vibrational spectra of biomolecules using atomistic simulations
Frontiers in Bioscience, 2009
Introduction 2.1. Potential energy surfaces for biomolecules 3. Harmonic approximation for large molecular systems 3.1. Harmonic model 3.2. Scaling procedures 4. Beyond the harmonic approximation 4.1. Molecular-dynamics simulations 4.2. Perturbative approaches to anharmonicity 4.3. CC-VSCF towards solving the full-dimensional schrödinger equation 5. Applications 6. Perspectives 7. Acknowledgments 8. References
Calculation of anharmonic vibrational spectroscopy of small biological molecules
PhysChemComm, 2002
The role of anharmonic effects in the vibrational spectroscopy of small biological molecules and their 1 : 1 complexes with water is discussed. The strengths and limitations of the vibrational self-consistent field (VSCF) method and its extensions as a computational tool for this purpose are examined. Anharmonic coupling between different vibrational modes is found to be very important for these systems, even for fundamental transitions, and incorporation of these effects seems essential for quantitative interpretation of experimental data. Both analytical, empirical force fields, and potential surfaces computed from electronic structure methods are used in VSCF calculations of several benchmark systems and compared with experimental spectroscopic data. Glycine in several conformers, the glycine-water complex, and N-methylacetamide are among the systems discussed. The main conclusions are: (1) Electronic structure methods such as MP2/DZP and density functional B97, give very good agreement with experimental data. Thus, MP2 and B97 clearly provide an accurate description of the anharmonic interactions. VSCF calculations, including all modes, with MP2, B97 and other successful methods are presently feasible for molecules with up to 15-20 atoms. (2) The electronic structure methods seem to give spectroscopic predictions in much better accord with experiment than standard empirical force fields such as AMBER or OPLS. The anharmonic couplings provided by these methods differ greatly, in the cases tested to date, from the ab initio ones. The implications of these results for future modeling of small biomolecules are discussed. Comments are provided on future directions in this subject, including extensions to large biomolecules.
All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins
Journal of Physical Chemistry B, 1998
New protein parameters are reported for the all-atom empirical energy function in the CHARMM program. The parameter evaluation was based on a self-consistent approach designed to achieve a balance between the internal (bonding) and interaction (nonbonding) terms of the force field and among the solvent-solvent, solvent-solute, and solute-solute interactions. Optimization of the internal parameters used experimental gas-phase geometries, vibrational spectra, and torsional energy surfaces supplemented with ab initio results. The peptide backbone bonding parameters were optimized with respect to data for N-methylacetamide and the alanine dipeptide. The interaction parameters, particularly the atomic charges, were determined by fitting ab initio interaction energies and geometries of complexes between water and model compounds that represented the backbone and the various side chains. In addition, dipole moments, experimental heats and free energies of vaporization, solvation and sublimation, molecular volumes, and crystal pressures and structures were used in the optimization. The resulting protein parameters were tested by applying them to noncyclic tripeptide crystals, cyclic peptide crystals, and the proteins crambin, bovine pancreatic trypsin inhibitor, and carbonmonoxy myoglobin in vacuo and in crystals. A detailed analysis of the relationship between the alanine dipeptide potential energy surface and calculated protein φ, angles was made and used in optimizing the peptide group torsional parameters. The results demonstrate that use of ab initio structural and energetic data by themselves are not sufficient to obtain an adequate backbone representation for peptides and proteins in solution and in crystals. Extensive comparisons between molecular dynamics simulations and experimental data for polypeptides and proteins were performed for both structural and dynamic properties. Energy minimization and dynamics simulations for crystals demonstrate that the latter are needed to obtain meaningful comparisons with experimental crystal structures. The presented parameters, in combination with the previously published CHARMM all-atom parameters for nucleic acids and lipids, provide a consistent set for condensed-phase simulations of a wide variety of molecules of biological interest.
2015
Intermolecular potential energy surface (IPS) for protein — protein has been examined using RHF, DFT-B3LYP and MP2 levels of theory with 6-31G, 6-31G* basis sets. A number of basis sets were used in order to evaluate the basis set effects, at all three levels of theory, basis sets has significant effects on the calculated potential energy curves (including position, depth and width of the potential well). Counterpoise (CP) correction has been used to show the extent of the basis set superposition error (BSSE) on the potential energy curves obtained for protein — protein system. The deepest BSSE-corrected potential well have been obtained at B3LYP level of theory with 6-31G basis set. The second virial coefficients calculated this way are fitted to the initial coefficients B2 varying E and ro, eventually some other parameters. * . Corresponding author: E-mail: m_monajjemi @Yahoo.com 175 Edited with the trial version of Foxit Advanced PDF Editor To remove this notice, visit: www.foxit...
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
A simplified force field for describing vibrational protein dynamics over the whole frequency range
The Journal of Chemical Physics, 1999
The empirical force fields used for protein simulations contain short-ranged terms (chemical bond structure, steric effects, van der Waals interactions) and long-ranged electrostatic contributions. It is well known that both components are important for determining the structure of a protein. We show that the dynamics around a stable equilibrium state can be described by a much simpler midrange force field made up of the chemical bond structure terms plus unspecific harmonic terms with a distance-dependent force constant. A normal mode analysis of such a model can reproduce the experimental density of states as well as a conventional molecular dynamics simulation using a standard force field with long-range electrostatic terms. This finding is consistent with a recent observation that effective Coulomb interactions are short ranged for systems with a sufficiently homogeneous charge distribution.
Molecular simulations using spherical harmonics
Chinese Journal of Chemistry, 2010
Computer-aided drug design is to develop a chemical that binds to a target macromolecule known to play a key role in a disease state. In recognition of ligands by their protein receptors, molecular surfaces are often used because they represent the interacting part of molecules and they should reflex the complementarity between ligand and receptor. However, assessing the surface complementarity by searching all relative position of two surfaces is often computationally expensive. The complementarity of lobe-hole is very important in protein-ligand interactions. Spherical harmonic models based on expansions of spherical harmonic functions were used as a fingerprint to approximate the binding cavity and the ligand , respectively. This defines a new way to identify the complementarity between lobes and holes. The advantage of this method is that two spherical harmonic surfaces to be compared can be defined separately. This method can be used as a filter to eliminate candidates among a large number of conformations, and it w i l l speed up the docking procedure. Therefore, it is possible to select complementary ligands or complementary conformations of a ligand and the macromolecules, by comparing their fingerprints previously stored in a database.
Protein signatures using electrostatic molecular surfaces in harmonic space
PeerJ, 2013
We developed a novel method based on the Fourier analysis of protein molecular surfaces to speed up the analysis of the vast structural data generated in the postgenomic era. This method computes the power spectrum of surfaces of the molecular electrostatic potential, whose three-dimensional coordinates have been either experimentally or theoretically determined. Thus we achieve a reduction of the initial three-dimensional information on the molecular surface to the one-dimensional information on pairs of points at a fixed scale apart. Consequently, the similarity search in our method is computationally less demanding and significantly faster than shape comparison methods. As proof of principle, we applied our method to a training set of viral proteins that are involved in major diseases such as Hepatitis C, Dengue fever, Yellow fever, Bovine viral diarrhea and West Nile fever. The training set contains proteins of four different protein families, as well as a mammalian representative enzyme. We found that the power spectrum successfully assigns a unique signature to each protein included in our training set, thus providing a direct probe of functional similarity among proteins. The results agree with established biological data from conventional structural biochemistry analyses. Lindahl E, Hess B, van der Spoel D. 2001. GROMACS 3.0: a package for molecular simulation and trajectory analysis. Journal of Molecular Modelling 7:306-317. Mayr G, Domingues FS, Lackner P. 2007. Comparative analysis of protein structure alignments. . Vangelatos I, Vlachakis D, Sophianopoulou V, Diallinas G. 2009. Modelling and mutational evidence identify the substrate binding site and functional elements in APC amino acid transporters. Molecular Membrane Biology 26(5-7):356-370