Bulletin of the American Physical Society
2009 APS March Meeting
Volume 54, Number 1
Monday–Friday, March 16–20, 2009; Pittsburgh, Pennsylvania
Session L39: Focus Session: Theories and Simulations for Biomolecular Dynamics in Cell-like Environments |
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Sponsoring Units: DBP Chair: Margaret Cheung, University of Houston Room: 411 |
Tuesday, March 17, 2009 2:30PM - 2:42PM |
L39.00001: Biochemistry on a leash: Confinement as a regulatory mechanism for bimolecular reaction rates Daniel Reeves, Keith Cheveralls, Jane Kondev We describe two mechanisms by which confinement regulates diffusion-limited bimolecular reaction rates. The first mechanism, illustrated by the actin capping protein formin, uses a flexible polymer to tether ligand binding sites, which serve as intermediaries, to the reactive site. The second mechanism uses a potential (e.g. hard wall potential), to constrain the motion of a ligand receptor within a confining volume. We analyze both mechanisms theoretically, using a combination of analytic and numerical techniques, to obtain the steady state binding kinetics. We explore how the reaction rates are regulated by parameters of the model such as the length of the polymer tether, and use our findings to explain the key features of the formin system. Finally, we suggest other systems, both synthetic and biological, in which these mechanisms for regulating bimolecular reactions might be at play. [Preview Abstract] |
Tuesday, March 17, 2009 2:42PM - 3:18PM |
L39.00002: Crowded, cell-like environment induces shape changes in aspherical protein Invited Speaker: How the crowded environment inside cells affects the structures of proteins with aspherical shapes is a vital question because many proteins and protein--protein complexes \textit{in vivo }adopt anisotropic shapes. Here we address this question by combining computational and experimental studies of a football-shaped protein (i.e. \textit{Borrelia burgdorferi }VlsE) under crowded, cell-like conditions. The results show that macromolecular crowding affects protein-folding dynamics as well as overall protein shape. In crowded milieus, distinct conformational changes in VlsE are accompanied by secondary structure alterations that lead to exposure of a hidden antigenic region. Our work demonstrates the malleability of ``native'' proteins and implies that crowding-induced shape changes may be important for protein function and malfunction \textit{in vivo}. [Preview Abstract] |
Tuesday, March 17, 2009 3:18PM - 3:30PM |
L39.00003: Molecular dynamics simulation study of multimerization of the Mms6 protein from Magnetospirillum magneticum strain AMB-1 Monica Lamm, Rastko Sknepnek, Lijun Wang, Marit Nilsen-Hamilton In order to optimize their search for nutrients, magnetotactic bacteria have developed an ability to align themselves to Earth's magnetic field. This is achieved by forming a chain of vesicles containing magnetite superparamagnetic nanoparticles with sizes of the order of 50nm. The presence of the small protein Mms6 plays an important role in the successful in vitro growth of magnetite nanoparticles, although the mechanism of this process is not understood. Preliminary experiments on Mms6 in solution indicate that the protein forms multimers of variable sizes, depending on the salt concentration. Using an intermediate level coarse grained model for Mms6 we investigated the formation of these multimers as a function of temperature and salt concentration. [Preview Abstract] |
Tuesday, March 17, 2009 3:30PM - 4:06PM |
L39.00004: The Packing of Flexible Screws and the Self-Limited Assembly of Biopolymer Bundles Invited Speaker: Living cells rely heavily on assemblies of filamentous proteins, such as F-actin and microtubules, to perform a variety of tasks, ranging from adhesion and locomotion to cell division and intracellular transport. In the dynamic cellular environment, the efficiency of these tasks is crucially dependent on the robust assembly and disassembly of rope-like bundles of filamentous molecules. Recent {\it in vitro} studies of F-actin assembly [Lai {\it et al.}, Phys. Rev. Lett. (2007)] suggest that bundle formation may take place as an equilibrium process, with a thermodynamically-preferred bundle diameter. Within the context of a generalized elastic model of filament packings, we explore the possibility that limited-bundle growth is directly linked with the intrinsic chiral structure of biological filaments themselves. The hexagonal packing of biopolymers leads to the build up of chiral stress, or torque, that generically induces the formation of twisting filament bundles of finite size. We demonstrate that the underlying elasticity of the bundle--i.e. whether hexagonal-solid or hexagonal-columnar--plays a key role in dictating both the thermodynamics (i.e. disperse, bundled or bulk aggregation) and structure (i.e. size and twist) of ``self-braiding" aggregates of helical filaments. [Preview Abstract] |
Tuesday, March 17, 2009 4:06PM - 4:18PM |
L39.00005: Simulation of signal transduction in model multiprotein systems Julius Su To simulate the dynamics of multiprotein machines, I have developed a method called multiconformer Brownian dynamics (mcBD). In this method, proteins rotate and translate via Brownian motion while their conformations are varied among a prestored set of structures on a simplified energy landscape, taking into account inter-protein interactions. As an example, I build a simple model of a G-protein coupled receptor/G-protein complex, and show that ligand binding causes conformational shifts, which induce GDP to leave, GTP to bind, and the complex to dissociate. The two proteins couple their fast fluctuations together into large-scale coordinated functional motions, resulting in signal transduction. I vary the shapes, electrostatics, and energy landscapes of the proteins independently and examine the impact this has on the system's function. In one result, increasing the binding between proteins improves the fidelity of communication, but at the expense of overall switching frequency. [Preview Abstract] |
Tuesday, March 17, 2009 4:18PM - 4:30PM |
L39.00006: Implicit solvent model for linear-scaling first-principles electronic structure calculations Hatem H. Helal, Mike Payne, Arash A. Mostofi Density functional theory (DFT) enables first-principles calculations that exhibit cubic scaling of the computational time required with respect to the number of atoms in the system. This presents an unavoidable difficulty when first-principles accuracy is needed for the study of large-scale biological systems. The ONETEP program reformulates DFT so that the required computational effort scales only linearly with system size, recently demonstrated for up to 32,000 atoms on 64 cores.\footnote{N.~D.~M.~Hine, P.~D.~Haynes, A.~A.~Mostofi, C.-K.~Skylaris and M.~C.~Payne, submitted to \emph{J.~Chem.~Phys.} (2008).} Further complicating DFT based studies of biomolecular systems is the need for an accurate representation of the electrostatic environment. Rather than introducing explicit solvent molecules into the system, which would be computationally prohibitive, we present our recent efforts to integrate an implicit solvent model\footnote{D.~A. Scherlis \emph{et al.}, \emph{J.~Chem.~Phys.} \textbf{124}, 074103 (2006).} with ONETEP in order to study systems in solution consisting of many thousands of atoms. We report preliminary results of our methodology with a study of the DNA nucleosome core particle. [Preview Abstract] |
Tuesday, March 17, 2009 4:30PM - 4:42PM |
L39.00007: Using stochastic dynamics to validate runtimes of protein simulations Stephen D. Hicks, Christopher L. Henley We use short molecular dynamics simulations ($\sim$200 cpu-hr, using NAMD) of individual bonds between capsid proteins to microscopically determine coarse-grained elastic parameters of entire virus capsids. In particular, we treat each protein (or for larger proteins, each domain) as a rigid body described by a 6-vector of translational and orientational degrees of freedom, $x_i(t)$. We then model the evolution of the relative positions as an overdamped random walk, $\dot x_i(t) = -\Gamma_{ij}K_{jk}(x_k(t)-\bar x_k) + \zeta_i(t)$, where $\zeta_i(t)$ are random variables satisfying $\langle\zeta_i(t)\zeta_j(t')\rangle = 2\Gamma_{ij}T\delta(t-t')$. Our goal is to determine the stiffness matrix $K_{ij}$, but this requires long-time data to measure accurately. We therefore measure the noise matrix $2\Gamma_{ij}T$, which depends on much shorter timescales, and compute the relaxation times by diagonalizing $\Gamma^{\frac12}K\Gamma^{\frac12}$. Although we use biologically relevant configurations in each simulation, we have taken the domains out of their full context by simulating one pair at a time, and therefore external stresses are missing, which we measure from the drift and compensate for in subsequent simulations. Finally, we apply this technique to the HIV capsid protein. [Preview Abstract] |
Tuesday, March 17, 2009 4:42PM - 4:54PM |
L39.00008: A symplectic integration method for elastic filaments Tony Ladd, Gaurav Misra Elastic rods are a ubiquitous coarse-grained model of semi-flexible biopolymers such as DNA, actin, and microtubules. The Worm-Like Chain (WLC) is the standard numerical model for semi-flexible polymers, but it is only a linearized approximation to the dynamics of an elastic rod, valid for small deflections; typically the torsional motion is neglected as well. In the standard finite-difference and finite-element formulations of an elastic rod, the continuum equations of motion are discretized in space and time, but it is then difficult to ensure that the Hamiltonian structure of the exact equations is preserved. Here we discretize the Hamiltonian itself, expressed as a line integral over the contour of the filament. This discrete representation of the continuum filament can then be integrated by one of the explicit symplectic integrators frequently used in molecular dynamics. The model systematically approximates the continuum partial differential equations, but has the same level of computational complexity as molecular dynamics and is constraint free. Numerical tests show that the algorithm is much more stable than a finite-difference formulation and can be used for high aspect ratio filaments, such as actin. We present numerical results for the deterministic and stochastic motion of single filaments. [Preview Abstract] |
Tuesday, March 17, 2009 4:54PM - 5:06PM |
L39.00009: Biomolecular Structure Determination with Divide and Concur Yoav Kallus, Veit Elser Divide and concur ($D-C$) is a general computational approach, designed for the solution of highly frustrated problems. Recently applied to the problems of disk packing, the kissing number problem, and 3-SAT, it was competitive or outperformed special-purpose methods.\footnote{S. Gravel and V. Elser, Phys. Rev. E 78, 036706 (2008)} We present a method for applying the $D-C$ framework to the problem of biomolecular structure determination. From a list of geometric constraints on groups of atoms in the molecule, we construct a deterministic iterative map that efficiently searches for structures simultaneously satisfying all constraints. As our method eschews an energy function and its minimization to focus on geometric constraints, it can very naturally integrate with the geometric constraints due to chemistry and physics, experimental constraints due to NMR data or many other experimental or biological hints. We present some results of our method. [Preview Abstract] |
Tuesday, March 17, 2009 5:06PM - 5:18PM |
L39.00010: Adaptive anisotropic network model: generating transition pathways of supramolecular system Zheng Yang, Ivet Bahar Generating of functional transition pathways of biomolecular systems is often complicated. This task becomes even more challenging in exploring systems of the order of megadaltons. Coarse-grained models that lend themselves to analytical solutions appear to be the only possible means of approaching such cases. We introduce a new method, \textit{adaptive anisotropic network model} ($a$ANM) for exploring functional transitions, based on the elastic network models, which have been widely used to describe the collective dynamics of biomolecular systems. Application to bacterial chaperonin GroEL highlights the utility of the methodology. Comparisons with experimental data and results from action minimization algorithm support the utility of $a$ANM as a computationally efficient, yet physically plausible, tool for unraveling potential transition pathways sampled by large complexes/assemblies and assessing the critical inter-residue interactions formed/broken near the transition state(s), most of which involve conserved residues. [Preview Abstract] |
Tuesday, March 17, 2009 5:18PM - 5:30PM |
L39.00011: Generic Coarse-Grained Model for Protein Folding and Aggregation Tristan Bereau, Markus Deserno The complexity involved in protein structure is not only due to the rich variety of amino acids, but also the inherent weak interactions, comparable to thermal energy, and important cooperative phenomena. This presents a challenge in atomistic simulations, as it is associated with high-dimensionality and ruggedness of the energy landscape as well as long equilibration times. We have recently developed a coarse-grained (CG) implicit solvent peptide model which has been designed to reproduce key consequences of the abovementioned weak interactions. Its intermediate level of resolution, four beads per amino acid, allows for accurate sampling of local conformations by designing a force field that relies on simple interactions. A realistic ratio of $\alpha$-helix to $\beta$-sheet content is achieved by mimicking a nearest-neighbor dipole interaction. We tune the model in order to fold helical proteins while systematically comparing the structure with NMR data. Very good agreement is achieved for proteins that have simple tertiary structures. We further probe the effects of cooperativity between amino acids by looking at peptide aggregation, where hydrophobic peptide fragments cooperatively form large-scale $\beta$-sheet structures. The model is able to reproduce features from atomistic simulations on a qualitative basis. [Preview Abstract] |
Tuesday, March 17, 2009 5:30PM - 5:42PM |
L39.00012: Computational Investigation of Conformational Changes in Proteins upon Adsorption Sumit Sharma, Gaurav Anand, Georges Belfort, Sanat K. Kumar Amyloidogenic diseases, such as, Alzheimer's, are caused by adsorption and aggregation of partially unfolded proteins. Protein adsorption is often accompanied by conformational rearrangements, which are thought to affect many properties such as their adhesion strength to the surface, biological activity, and aggregation tendency. Experiments have shown that many proteins, upon adsorption to hydrophobic surfaces, undergo a helix to sheet or random coil secondary structural rearrangement. To better understand the equilibrium structural complexities of this phenomenon, we have performed Monte Carlo (MC) simulations and Single Chain Mean Field calculations of adsorption of different proteins, modeled as lattice chains, to study the adsorption behavior and equilibrium protein conformations at different temperatures, protein concentration and surface hydrophobicity. Free energy and entropic effects on adsorption have been studied by determining density of states using Weighted Histogram Analysis Method. Conformational transitions of proteins on surfaces will be discussed as a function of surface hydrophobicity. [Preview Abstract] |
Tuesday, March 17, 2009 5:42PM - 5:54PM |
L39.00013: Role of van der Waals interactions for the intrinsic stability of polyalanine helices Alexandre Tkatchenko, Volker Blum, Joel Ireta, Matthias Scheffler The helical motif is an ubiquitous conformation adopted by aminoacid residues in a protein structure and helix formation is the simplest example of the protein folding process. How stable is the folded peptide helix in comparison to a random coil structure? What are the interactions responsible for stabilizing the helical conformation? Answering these questions has thus a direct implication for understanding protein folding. In this work we use density functional theory (DFT) augmented with a non-empirical correction for van der Waals (vdW) forces to study the stability of alanine polypeptide helices \textit{in vacuo}. We find a large stabilization of the native helical forms when vdW correction is used. It amounts to 121\%, 157\% and 83\% on top of the Perdew-Burke-Ernzerhof (PBE) functional in the case of infinite $\alpha$, $\pi$ and 3$_{10}$ helices, respectively. Thus, the experimentally observed $\alpha$ helix is significantly stabilized by vdW forces both over the fully extended and the 3$_{10}$ conformations. Our findings also suggest an explanation to the remarkable stability of gas-phase alanine helices up to high temperatures [M. Kohtani \textit{et al.} JACS 126, 7420 (2004)]. [Preview Abstract] |
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