Bulletin of the American Physical Society
2006 APS March Meeting
Monday–Friday, March 13–17, 2006; Baltimore, MD
Session A26: Biomolecular Computation |
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Sponsoring Units: DBP Chair: Thomas Darden, National Institute of Health Room: Baltimore Convention Center 323 |
Monday, March 13, 2006 8:00AM - 8:12AM |
A26.00001: Quantum Mechanical Study of C-Terminal Cleavage Reaction in Inteins Philip Shemella, Saroj Nayak, Brian Pereira, Shekhar Garde, Georges Belfort, Patrick Van Roey, Vicky Derbyshire, Marlene Belfort Although inteins undergo autocatalytic cleaving and splicing reactions via a relatively well accepted reaction scheme, the mechanism that induces these reactions is not well understood. The reactions can be prevented or speeded up through mutations of various critical amino acids proximal to the active site or through changes in the solution pH and/or temperature. We are interested in obtaining an atomic level understanding of the C-terminal cleavage reaction using quantum mechanical reaction simulation techniques. The reaction is based on the highly conserved catalytic module of histidine-asparagine-cysteine. Experimentally, intein C-terminal cleavage occurs more readily at low pH and high temperature. Working closely with experimentalists, we use a combination of gas phase and implicit solvent techniques with density functional theory to compare energy barriers for various proposed mechanisms. The mechanism with the lowest energy barrier is consistent with experimental results and is based on the protonation of the peptide amide by a hydronium ion and the subsequent cyclization of the asparagine amino acid, resulting in cleavage of the peptide bond. [Preview Abstract] |
Monday, March 13, 2006 8:12AM - 8:24AM |
A26.00002: Evolutionary Strategies for Protein Folding Srinivasa Murthy Gopal, Wolfgang Wenzel The free energy approach for predicting the protein tertiary structure describes the native state of a protein as the global minimum of an appropriate free-energy forcefield. The low-energy region of the free-energy landscape of a protein is extremely rugged. Efficient optimization methods must therefore speed up the search for the global optimum by avoiding high energy transition states, adapt large scale moves or accept unphysical intermediates. Here we investigate an evolutionary strategies(ES) for optimizing a protein conformation in our all-atom free-energy force field([1],[2]). A set of random conformations is evolved using an ES to get a diverse population containing low energy structure. The ES is shown to balance energy improvement and yet maintain diversity in structures. The ES is implemented as a master-client model for distributed computing. Starting from random structures and by using this optimization technique, we were able to fold a 20 amino-acid helical protein and 16 amino-acid beta hairpin[3]. We compare ES to basin hopping method. \newline[1]T. Herges and W. Wenzel,Biophys.J. {\bf 87},3100(2004) \newline[2] A. Verma and W. Wenzel {\it Stabilization and folding of beta-sheet and alpha-helical proteins in an all-atom free energy model}(submitted)(2005) \newline[3] S. M. Gopal and W. Wenzel {\it Evolutionary Strategies for Protein Folding} (in preparation) [Preview Abstract] |
Monday, March 13, 2006 8:24AM - 8:36AM |
A26.00003: Towards predictive molecular dynamics simulations of DNA: electrostatics and solution/crystal environments Volodymr Babin, Jason Baucom, Thomas Darden, Celeste Sagui We have investigated to what extend molecular dynamics (MD) simulatons can reproduce DNA sequence-specific features, given different electrostatic descriptions and different cell environments. For this purpose, we have carried out multiple unrestrained MD simulations of the duplex d(CCAACGTTGG)2. With respect to the electrostatic descriptions, two different force fields were studied: a traditional description based on atomic point charges and a polarizable force field. With respect to the cell environment, the difference between crystal and solution environments is emphasized, as well as the structural importance of divalent ions. By imposing the correct experimental unit cell environment, an initial configuration with two ideal B-DNA duplexes in the unit cell is shown to converge to the crystallographic structure. To the best of our knowledge, this provides the first example of a multiple nanosecond MD trajectory that shows and ideal structure converging to an experimental one, with a significant decay of the RMSD. [Preview Abstract] |
Monday, March 13, 2006 8:36AM - 8:48AM |
A26.00004: Coarse-grained model of chaperonin-mediated protein folding George Stan, D. Thirumalai, George Lorimer, Bernard Brooks Chaperonins are biological nanomachines that employ a spectacular mechanism for simulated annealing. During the chaperonin cycle, concerted, large scale, rigid body conformational changes, ultimately driven by ATP hydrolysis, result in a dramatically expanded chaperonin cavity serving as folding chamber. Chaperonins repeatedly bind misfolded proteins, randomly disrupt their structure, and release them in less folded states, allowing these substrate proteins multiple opportunities to find pathways leading to the native state. What is the fate of the non-native protein during the chaperonin cycle? We addressed this question using coarse-grained molecular dynamics simulations. We find that the fundamental annealing function of the GroEL chaperonin consists of forced unfolding and refolding of the substrate protein. The annealing action is related to the change in the nature of the interaction between the substrate protein and the GroEL particle from predominantly hydrophobic to largely hydrophilic. To identify the proteins most likely to be natural substrates for GroEL we use a bioinformatic approach. Our hypothesis is that natural substrates contain patterns of residues similar to the co-chaperonin GroES. [Preview Abstract] |
Monday, March 13, 2006 8:48AM - 9:00AM |
A26.00005: Using Molecular Dynamics simulations in the analysis of Electron Spin Resonance spectra Deniz Sezer, Benoit Roux ESR spectra from spin labeled sites in proteins are sensitive both to the conformations of the spin label at the labeled site and to its flexibility and rate of transition between multiple conformations. Even though measures of spin label mobility can be extracted directly from the spectrum, deducing the wealth of factors that affect the spectral line shape is impossible in most of the cases. Often, one has to model the motion of the spin label and calculate spectra for different values of the parameters of the model. From the work where this approach has been followed it appears that anisotropic Brownian diffusion in a restricting potential constitutes a good description of the spin label motion. This hydrodynamic depiction correlates poorly with the molecular structure of the spin label and its linker. To address this limitation, we combine MD simulations with stochastic models in the simulation of ESR spectra. This allows us to treat the structure and the fast dynamics of the spin label and its environment in atomistic detail, while handling the slower motional modes to which the spectrum is susceptible phenomenologically. We analyse the MD trajectories with the Redfield formalism, appropriate in the fast motional regime. The exchange between the populated rotamers of the spin label and the overall tumbling of the macromolecule, occurring on a longer time scale, are accounted for using stochastic dynamics. [Preview Abstract] |
Monday, March 13, 2006 9:00AM - 9:12AM |
A26.00006: Locating structural energy minimum of biological molecules in explicit solvent Eric Dykeman, Otto Sankey Biological molecules in waters often adopt several structural conformers. These structures correspond to the various local energy minima on the solute-solvent potential energy hyper-surface. Methods capable of predicting the various conformations that a molecule can adopt in solution have involved, (naming a few), annealing and replica exchange molecular dynamics simulations. However, implementation of these methods with systems containing explicit solvent still requires large amounts of computation time due to the requirement of a small time step. The recent development of the activation relaxation technique (ART) of Mousseau et al. provides an alternative that may reduce computational costs. Instead of following a Newtonian trajectory, ART locates local energy minima through a series of activations to energy saddles followed by relaxation to a local energy minimum. Here we discuss extensions of the method to explicit solvent models. This development and extension of the technique offers insight into how water affects the potential energy surface of molecules in solution. [Preview Abstract] |
Monday, March 13, 2006 9:12AM - 9:24AM |
A26.00007: Predicting 3D structures of transient protein-protein complexes Petras Kundrotas, Emil Alexov Predicting transient protein-protein complexes is a major task of the post genomic era since the ultimate goal is to understand how proteins interact in the living cell. Apparently experimental methods as X-ray and NMR cannot be used at such large scale and therefore numerical methods for predicting protein-protein complexes should be applied. In this presentation we propose homology based approach to predict 3D structure of protein complexes. The underlying presumption is that if two proteins are homologous to other two proteins that form a complex then they will form a complex, 3D structure of which should be similar to the 3D structure of the existing complex. In order to test our method we have created a database of template complexes. The methodology of database creation will be presented and discussed. Due to very limited number of protein-protein complexes in the Protein Data Bank we expanded our database by including proteins containing loosely connected domains. A jack-knife test was performed and the quality of the models was evaluated against existing protein-protein complexes. It is shown that including interfacial information and residue pairing restrains in the sequence alignment improves the results. [Preview Abstract] |
Monday, March 13, 2006 9:24AM - 9:36AM |
A26.00008: Charge transfers from Na atom in (H2O)n clusters and in water solution Takeshi Nozue, Junichi Hoshino, Kazuo Tsumuraya The charge state of sodium ions in water is an essential issue in both biophysical and physicochemical areas. Although the nominal charge state of sodium is +1 in water solution, the true charge is less than unity and will depend on the environments. We clarify the true charges states with ab initio density functional methods. There have been several methods to evaluate the charges that belong to each atom in molecules: Bader analysis divides up into regions where the dividing surfaces are at a minimum in the density. [1] The Bader charge analysis [2] has difficulty of finding all the critical points around the atom. Henkelman et al. have proposed a modified partition scheme. [3] We use a modified version of the Henkelman's scheme to integrate the core charge densities separately. The method gives the charge transfer from Na to H2O to be 0.167e and that to (H2O)2 to be 0.522e. The original Bader charge scheme gives 0.156e and 0.596e respectively. We present the transfers surrounded by a large number of water molecules and those in water solution in periodic system. [1]R.F.W.Bader, Atoms in Molecules: A Quantum Theory, Clarendon:Oxford. 1990. [2]C.F.Guerra, et al., J.Comp.Chem. 25, 189(2003). [3]G.Henkelman, et al., Comp. Mat. Sci. in press. [Preview Abstract] |
Monday, March 13, 2006 9:36AM - 9:48AM |
A26.00009: Coarse-graining protein energetics in sequence variables Fei Zhou, Gevorg Grigoryan, Amy Keating, Gerbrand Ceder, Dane Morgan We show that cluster expansions (CE), previously used to model solid-state materials with binary or ternary configurational disorder can be extended to the protein design problem. We present a generalized CE framework, in which properties such as energy can be unambiguously expanded in the amino-acid sequence space. The CE coarse grains over non-sequence degrees of freedom (e.g., side-chain conformations) and thereby simplifies the problem of designing proteins, or predicting the compatibility of a sequence with a given structure, by many orders of magnitude. The CE is physically transparent, and can be evaluated through linear regression on the energies of training sequences. [PRL 95, 148103 (2005)]. We show, as example, that good prediction accuracy is obtained with up to pairwise interactions for a coiled-coil backbone, and that triplet and/or quadruplet interactions are important in the energetics of the more globular zinc-finger and WW domain backbones. In the coiled-coil system, where experimental data is available, the calculated pair interaction parameters compare favorably with measured coupling energies. The clear advantage of a CE driven optimization over a direct one is demonstrated by searching for low-energy sequences on the zinc-finger backbone. Other possible applications of our approach are also discussed. [Preview Abstract] |
Monday, March 13, 2006 9:48AM - 10:00AM |
A26.00010: MAME Water Model: hydrogen bonding, electrostatic, polarization and van der Waals interactions in water. Eugene Tsiper Hydrogen bonding is key to many unusual properties of water and its role in biological systems. I will describe an elegant water model derived using the minimal atomic multipole expansion (MAME). The minimal set for water consists of three multipoles that are chosen to satisfy experimental molecular dipole and both components of the molecular quadrupole. Two atomic polarizabilities, $\alpha_O=1.4146$ A$^3$ and $\alpha_{\rm H}=0.0836$ A$^3$, reproduce all three components of the polarizability tensor due to a relation between the latter, which follows from the model and is indeed satisfied experimentally. The model thus based on the known monomer properties reproduces hydrogen bonding in the dimer and compares favorably to the best available water-water interaction potentials. I will also discuss the meaning of distributed polarizabilities for computing dispersion (van der Waals) interactions. The atomic polarizabilities in water yield reasonable dispersion energy of 1.4 kcal/mol, which is otherwise underestimated when water molecules are treated as polarizable points. [E.V. Tsiper, Phys. Rev. Lett. 94, 013204, 2005] [Preview Abstract] |
Monday, March 13, 2006 10:00AM - 10:12AM |
A26.00011: Accurate computation and interpretation of spin-dependent properties in metalloproteins Jorge Rodriguez Nature uses the properties of open-shell transition metal ions to carry out a variety of functions associated with vital life processes. Mononuclear and binuclear iron centers, in particular, are intriguing structural motifs present in many heme and non-heme proteins. Hemerythrin and methane monooxigenase, for example, are members of the latter class whose diiron active sites display magnetic ordering. We have developed a computational protocol based on spin density functional theory (SDFT) to accurately predict physico-chemical parameters of metal sites in proteins and bioinorganic complexes which traditionally had only been determined from experiment. We have used this new methodology to perform a comprehensive study of the electronic structure and magnetic properties of heme and non-heme iron proteins and related model compounds. We have been able to predict with a high degree of accuracy spectroscopic (M\"{o}ssbauer, EPR, UV-vis, Raman) and magnetization parameters of iron proteins and, at the same time, gained unprecedented microscopic understanding of their physico-chemical properties. Our results have allowed us to establish important correlations between the electronic structure, geometry, spectroscopic data, and biochemical function of heme and non- heme iron proteins. [Preview Abstract] |
Monday, March 13, 2006 10:12AM - 10:24AM |
A26.00012: Computational studies of a redox-driven proton pump: Cytochrome c oxidase and biological energy transduction Alexei A. Stuchebrukhov Cytochrome c oxidase (CcO) is a redox-driven proton pump, an energy converting molecular machine, which reduces atmospheric oxygen to water and couples the oxygen reduction reaction to the creation of a membrane proton gradient. The proton gradient subsequently drives the synthesis of ATP. The structure of the enzyme has been solved; however, the molecular mechanism of proton pumping is still poorly understood. The correlated electron and proton transport plays a crucial role in the function of the enzyme. Our computer simulations -- combined ab initio and classical, MD and MC- indicate a possible mechanism of CcO. We find that one of the His ligands of the catalytic site, and certain chains of water molecules inside of the enzyme play a crucial role. In this presentation, computational and experimental studies directed toward understanding the mechanism of cytochrome c oxidase will be discussed. D.M. Popovic and A.A. Stuchebrukhov, Proton pumping mechanism and catalytic cycle of cytochrome c oxidase: Coulomb pump model with kinetic gating, FEBS Lett. 2004. [Preview Abstract] |
Monday, March 13, 2006 10:24AM - 10:36AM |
A26.00013: Ab Initio QM/MM Study of the Ester-hydrolysis Reaction Mechanism in Haloalkane Dehalogenase Yiming Zhang, Yu Zhou, Saroj Nayak, Angel Garcia Ab Initio QM/MM calculations are used to investigate the ester-hydrolysis step of dichloroethane hydrolysis catalyzed by haloalkane dehalogenase. Amino acids around the active site (which includes ASP124, HIS289, ASP260, TRP125, TRP175), dichoroethane and water are treated by QM at a level of HF/6-31G(d,p). The remainder of the protein and solvent are treated classically. Two scenarios of hydrolysis mechanism for the alkyl-enzyme intermediate have been considered. In one, the HIS289-catalyzed water oxygen could be incorporated in the carboxylate group of ASP124, leading the cleavage of one of the original carbonyl bonds on ASP124. In the other, the ASP124 and HIS289 as general base, activate water as the nucleophilic agent, which attacks the alkyl carbon in substrate. The reaction paths and potential energy profiles are compared for both mechanisms. [Preview Abstract] |
Monday, March 13, 2006 10:36AM - 10:48AM |
A26.00014: Combining biophysical and bioinformatical approaches for predicting residue's contacts. Emil Alexov, Amber Allardice, Petras Kundrotas One of the most important task of the post genomics era is to utilize the enormous sequence information delivered from the genomes and to predict 3D structure of proteins. The quality of the predicted structure depends on many factors including the improvement made in ab initio, threading and homology modeling methods. Here we combine the method of correlated mutations with biophysical restrains in order to predict residue's contacts from amino acids sequence alone. The parameters of the protocol were optimized against a set of 21 proteins with known high resolution 3D structures. The effects of the degree of residue conservation, sequence similarity among the sequences within the multiple sequence alignment and conservation coefficient of two amino acids positions were studied. It was shown that the prediction accuracy of the method of correlated mutations alone is pure, on average only 10{\%} of the contacts are predicted correctly. However, adding biophysical filters greatly improves the accuracy of the predictions. Thus, implying pairing rules for charged, polar and hydrophobic residues significantly reduces the total number of the predictions, e.g. reduces the coverage, however, most of the rejected predictions are false positives. As result, the relative rate of the correct predictions increases. [Preview Abstract] |
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