Bulletin of the American Physical Society
2009 APS March Meeting
Volume 54, Number 1
Monday–Friday, March 16–20, 2009; Pittsburgh, Pennsylvania
Session V6: Recent Advances in Biomolecular Simulations |
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Sponsoring Units: DCOMP Chair: Jerry Bernholc, North Carolina State University Room: 406 |
Thursday, March 19, 2009 8:00AM - 8:36AM |
V6.00001: Metadynamics simulation of large scale motion in proteins Invited Speaker: Understanding large scale protein motions is essential in the study of many biological processes. Molecular dynamics simulations could provide important clues, but they are hampered by the fact, that they can only explore time scales, smaller than most interesting phenomena. To circumvent this problem, our group has developed a number of enhanced sampling techniques that allow exploring many such long time scale phenomena. In particular, a very recent development permits reconstructing complex pathways without the need of introducing collective variable. A number of large scale applications will be presented. [Preview Abstract] |
Thursday, March 19, 2009 8:36AM - 9:12AM |
V6.00002: Quantum Simulations of Solvated Biomolecules Using Hybrid Methods Invited Speaker: One of the most important challenges in quantum simulations on biomolecules is efficient and accurate inclusion of the solvent, because the solvent atoms usually outnumber those in the biomolecule of interest. We have developed a hybrid method that allows for explicit quantum-mechanical treatment of the solvent at low computational cost. In this method, Kohn-Sham (KS) density functional theory (DFT) is combined with an orbital-free (OF) DFT. Kohn-Sham (KS) DFT is used to describe the biomolecule and its first solvation shells, while the orbital-free (OF) DFT is employed for the rest of the solvent. The OF part is fully O(N) and capable of handling 10$^5$ solvent molecules on current parallel supercomputers, while taking only $\sim$ 10 \% of the total time. The compatibility between the KS and OF DFT methods enables seamless integration between the two. In particular, the flow of solvent molecules across the KS/OF interface is allowed and the total energy is conserved. As the first large-scale applications, the hybrid method has been used to investigate the binding of copper ions to proteins involved in prion (PrP) and Parkinson's diseases. Our results for the PrP, which causes mad cow disease when misfolded, resolve a contradiction found in experiments, in which a stronger binding mode is replaced by a weaker one when concentration of copper ions is increased, and show how it can act as a copper buffer. Furthermore, incorporation of copper stabilizes the structure of the full-length PrP, suggesting its protective role in prion diseases. For alpha-synuclein, a Parkinson's disease (PD) protein, we show that Cu binding modifies the protein structurally, making it more susceptible to misfolding -- an initial step in the onset of PD. In collaboration with W. Lu, F. Rose and J. Bernholc. [Preview Abstract] |
Thursday, March 19, 2009 9:12AM - 9:48AM |
V6.00003: Urea's action on the hydrophobic interaction in physical and biophysical systems Invited Speaker: For more than a century, urea has been commonly used as an agent for denaturing proteins. However, the mechanism behind its denaturing power is still not well understood. The mechanism of denaturation of proteins by urea is explored using all-atom microseconds molecular dynamics simulations of hen lysozyme generated on BlueGene/L. Accumulation of urea around lysozyme shows that water molecules are expelled from the first hydration shell of the protein. We observe a two stage penetration of the protein, with urea penetrating the hydrophobic core before water, forming a ``dry globule." The direct dispersion interaction between urea and the protein backbone and sidechains is stronger than for water, which gives rise to the intrusion of urea into the protein interior and also to urea's preferential binding to all regions of the protein. This is augmented by preferential hydrogen bond formation between the urea carbonyl and the backbone amides which contributes to the breaking of intra-backbone hydrogen bonds. Our study supports the ``direct interaction mechanism" whereby urea has a stronger dispersion interaction with protein than water. We also show by molecular dynamics simulations that a 7 M aqueous urea solution unfolds a chain of purely hydrophobic groups which otherwise adopts a compact structure in pure water. The unfolding process arises due to a weakening of hydrophobic interactions between the polymer groups. Again the action of urea is found to be direct, through its preferential binding to the polymer or plates. It is, therefore, acting like a surfactant capable of forming hydrogen bonds with the solvent. The preferential binding and the consequent weakened hydrophobic interactions are driven by enthalpy and are related to the difference in the strength of the attractive dispersion interactions of urea and water with the polymer chain or plate. We also show that the indirect mechanism, in which urea acts as a chaotrope, is not a likely cause of urea's action as a denaturant. These findings suggest that, in denaturing proteins, urea (and perhaps other denaturants) forms stronger attractive dispersion interactions with the protein side chains and backbone than does water and, therefore, is able to dissolve the core hydrophobic region. [Preview Abstract] |
Thursday, March 19, 2009 9:48AM - 10:24AM |
V6.00004: Systematic Coarse-Graining of Biomolecular Systems Invited Speaker: A multiscale theoretical and computational methodology will be presented for studying biomolecular systems across multiple length and time scales. The approach provides a systematic connection between all-atom molecular dynamics, coarse-grained modeling, and mesoscopic phenomena. At the heart of the methodology is the multiscale coarse-graining method for rigorously deriving coarse-grained models from the underlying molecular-scale forces. Applications of the multiscale approach will be given for membranes and proteins. Recent advances in coarse-graining large protein complexes will also be described along with key applications. [Preview Abstract] |
Thursday, March 19, 2009 10:24AM - 11:00AM |
V6.00005: Multi-resolution protein modeling by combining theory and experiment Invited Speaker: The detailed characterization of the overall free energy landscape associated with the folding process of a protein is the ultimate goal in protein folding studies. Modern experimental techniques provide accurate thermodynamic and kinetic measurements on restricted regions of a protein landscape. Although simplified protein models can access larger regions of the landscape, they are oftentimes built on assumptions and approximations that affect the accuracy of the results. We present new methodologies that allows to combine the complementary strengths of theory and experiment for a more complete characterization of a protein folding landscape at multiple resolutions. Recent results and possible applications will be discussed. [Preview Abstract] |
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