Advanced Biomolecular Simulations - Development and Applications
EMSL Project ID
30994
Abstract
This project focuses on two important components of biomolecular modeling and simulation: i) the development of novel molecular modeling capabilities and their efficient parallel implementations, and ii) the application of these capabilities for the study of environmentally important complex biological systems. Our research will focus on massively parallel implementations of methodologies that enable peptide and protein simulations at significantly larger scales compared to current applications, in the time and spatial domains, as well as in the complexity of interaction models for large, heterogeneous biomolecular assemblies. These include the implementation of multi-ensemble technologies, such as replica-exchange, in the NWChem framework, with the promise of reaching high scalability in molecular dynamics simulations for highly complex systems. The second methodology targeted in this project is further development of Brownian dynamics methodology to allow millisecond time-scale simulations of multi-protein complexation. This will be implemented in the SDAMM software, based on the concept of the Simulation of Diffusional Association (SDA) program for systems consisting of rigid protein domains with or without flexible linkers between them with modeling of the forces between the rigid domains based on their atomic detail structures. These methodologies will be applied to molecular simulations of a number of environmentally important biomolecular systems. We will continue our work on characterizing the effect of the Gram negative lipopolysaccharide outer membranes on the stability and dynamics of transmembrane proteins. The primary focus is on a characterization of the free energy profile for material transport across the membrane through porins and protein channels by calculation of the potentials of mean force of ions and small molecules moving through transmembrane ion channel proteins and specific and non-specific porins. We will investigate the effect of environmental, ionic compounds on the structural integrity of the Gram-negative microbial outer membrane of the environmentally ubiquitous microbe Pseudomonas aeruginosa. The second system to be studied is the MHC class I proteins which are of great importance for the fundamental understanding of the interaction of the immune system with the environment and changes of the environment. These are membrane-bound proteins of the immune system that present antigenic peptides at the cell surface for which peptide loading in the endoplasmic reticulum is a crucial step involving interactions with several proteins to form a nano-molecular loading complex. We will investigate the coupling of conformational flexibility and loading characteristics in long time replica exchange MD simulations. The Brownian dynamics capabilities will be demonstrated in studies of multi-domain signaling proteins and how post-translational modification of flexible as well as rigid parts affects their structure, dynamics, and interactions and therefore function. This model is also applicable to membrane attached proteins often involving flexible regions and domain reorganizations. The simulation of protein solutions is important to understand phenomena such as cellular crowding or protein mixtures. The application components will be reported in the peer-reviewed scientific literature.
Project Details
Project type
Capability Research
Start Date
2008-10-03
End Date
2011-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Kannan S, and MW Zacharias. 2011. "Role of the Closing Base Pair for d(GCA) Hairpin Stability: Free Energy Analysis and Folding Simulations ." Nucleic Acids Research.
Mereghetti P, and RC Wade. 2011. "Diffusion Of Hydrophobin Proteins In Solution And Interactions With A Graphite Surface." BMC Biophysics 4(9):, doi:10.1186/2046-1682-4-9
Mereghetti P, and RC Wade. 2012. "Atomic detail brownian dynamics simulations of concentrated protein solutions with a mean field treatment of hydrodynamic interactions." Journal of Physical Chemistry B 116(29):2523-2533. doi:10.1021/jp212532h
Mereghetti P, R Gabdoulline, and RC Wade. 2010. "Brownian Dynamics Simulation of Protein Solutions: Structural and Dynamical Properties." Biophysical Journal 99(11):3782-3791. doi:10.1016/j.bpj.2010.10.035
Physicochemical/Thermodynamic Framework for the Interpretation of Peptide Tandem Mass Spectra
William R. Cannon and Mitchell M. Rawlins
J. Phys. Chem. C,
Publication Date (Web): November 25, 2009
DOI: 10.1021/jp905049d
Schneider S, and MW Zacharias. 2012. "Combining Geometric Pocket Detection and Desolvation Properties to Detect Putative Ligand Binding Sites on Proteins." , Pacific Northwest National Laboratory, Richland, WA. doi:10.1016/j.jsb.2012.09.010 [Unpublished]
Sieker F, TP Straatsma, S Springer, and M Zacharias. 2008. "Differential tapasin dependence of MHC class I molecules correlates with conformational changes upon peptide dissociation: A molecular dynamics simulation study." Molecular Immunology 45(14):3714-3722. doi:10.1016/j.molimm.2008.06.009
Wu C, A Kalyanaraman, and WR Cannon. 2012. "pGraph: Efficient Parallel Construction of Large-Scale Protein Sequence Homology Graphs." IEEE Transactions on Parallel and Distributed Systems 23(10):1923-1933. doi:10.1109/TPDS.2012.19