Molecular Dynamics Simulations Of Biological Macromolecules

Heart, Lung, And Blood Institute

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Abstract

The Computational Biophysics Section studies problems of biological significance using several theoretical techniques: molecular dynamics, molecular mechanics, modeling, ab initio analysis of small molecule structure, and molecular graphics. These techniques are applied to a wide variety of macromolecular systems.[unreadable] [unreadable] Dr. Zheng, in collaboration with Jung-Chi Liao and Sebastian Doniach of Stanford University, has applied two of our recently developed computational analysis tools based on an elastic network model to probe the dynamical mechanism underlying the allosteric coupling between ATP binding and polynucleotide binding in the Hepatitis C virus NS3 helicase. This study has provided the structural and dynamic basis for the inch-worm like translocation mechanism of NS3.[unreadable] [unreadable] In collaboration with D. Thirumalai at U. Maryland, we have performed a normal mode analysis to explore the energetically favorable collective motions encoded in the bullet shaped double-ring structure of Escherichia coli chaperonin GroEL. We have identified a single mode that captures the highly intricate allosteric transition in GroEL, which is found to be most robust to parametric perturbations caused by sequence variations.[unreadable] [unreadable] Mr. O'Brien's research is focused on modeling and predicting the effect of osmolytes on protein folding kinetics and thermodynamics. Osmolytes are a class of small organic molecules that occur naturally in the human body. Depending on the type of osmolyte, and concentration, a protein's native state can be stabilized, destabilized or remain unchanged in an aqueous osmolyte solution. Combining experimental results of transfer free energies of individual amino-acids with coarse-grained protein simulations we have been able to qualitatively reproduce the effect of various osmolytes on the thermodynamics of protein folding. We are now using our newly developed models to study the impact of osmolytes on protein folding pathways and kinetics. Mr. O'Brien is also addressing the fundamental question of the origin of the osmophobic effect. In particular, using all-atom simulations he is testing the hypothesis that excluded volume (aka molecular crowding) interactions between osmolyte molecules and proteins give rise to the osmophobic effect.[unreadable] [unreadable] Another area of research Mr. O'Brien is focused on is the effect of molecular crowding on the formation of disease related proteins aggregates known as amyloid. Amyloid fibrils have been shown experimentally to grow via monomer addition. Using advanced sampling techniques, such as multi-Hamiltonian replica exchange, we are computing the free energy profile of monomer addition to the fibril in various crowding environments. In this way we can understand the impact of molecular crowding on the thermodynamics of amyloid growth.[unreadable] [unreadable] Dr. Klauda's research consists of collaborative work involving lipid dynamics and substrate transport in a membrane protein. Based on experimental collaboration with Dr. Klaus Gawrisch, the motions measured from 13C NMR in the 15-125 MHz range and up to 100 in length are dominated by fast isomerizations and a slower lipid wobble. Similar work with phosphorous NMR experimentalist, Prof. Alfred Redfield at Brandeis University and Prof. Mary Roberts at Boston College, suggest that what was believed to be a measure of lipid rotation about the major axis is actually a measure of lipid wobble. Through this joint venture with experimentalists, we were able to determine the rotational and wobble diffusion constants of DPPC in a lipid bilayer. [unreadable] [unreadable] Dr. Klauda is also studying the transport mechanisms of disaccharides in an important membrane protein of E. coli, lactose permease (LacY). Previously he has determined that the anomeric state of the sugar influences the binding conformations. Similarly, the ring structure influences interactions with the protein based on comparison studies with disaccharides with galactose and glucose. In collaboration with Dr. Alan Peterkofsky, structural changes towards the unknown outward facing structure of LacY have been observed in simulations with certain protein mutants. These results are the first indication of structural changes believed to be important in the overall transport cycle of this membrane protein[unreadable] [unreadable] Dr. Damjanovic's research focuses on study of the relationship between protein structure, dynamics and function. Due to a longer than microsecond timescale, the nature and pathways of conformational rearrangements in proteins are poorly understood. To tackle this problem, new methods that go beyond conventional molecular dynamics simulations need to be developed and benchmarked against experiments. Dr. Damjanovic is using the recently developed Self-Guided Langevin Dynamics (SGLD) simulation method to study conformational rearrangements induced by ligand binding in two proteins: staphylococcal nuclease (SN) and nitrogen regulatory protein C (NtrC). In variants of SN in which an ionizable group is buried in the protein interior, ionization of internal ionizable groups can trigger conformational rearrangements. SGLD simulations indicate changes in secondary structure that are consistent with experimental findings. This project is performed in collaboration with Prof. Bertrand Garcia-Moreno (JHU). NtrC can exist in two conformations: inactive and active. Binding of a phosphate group stabilizes the active form. SGLD simulations of this protein indicate large conformational heterogeneity in the region involved in structural transition, and records structures that are half-way between the two forms.[unreadable] [unreadable] Ms. Cobar's research has the ultimate goal of elucidating the active site and mechanism employed by particulate methane monooxygenase (p-MMO) to convert methane into methanol in nature. Several copper sites have been proposed as candidates for the active site. Ms. Cobar uses Quantum Mechanical/Molecular Mechanical (QM/MM) and Molecular Dynamics (MD) simulation techniques to model possible methane hydroxylation mechanisms at each of the proposed active sites. The calculations should reveal which active site and mechanism are the most energetically accessible to the protein-methane complex.[unreadable] [unreadable] Dr. Parry is carrying out molecular dynamics simulations of major histocompatibility molecules with bound peptide and in the unbound form. We have nanoseconds from each of the two complexes and are collecting more data in order to better sample conformational space. We have obtained optimized bond lengths and charge of i) phenyl based and ii) naphthalene based amino acid analogs. The phenyl based residues have a variety of common substituents at the C4 position, and the latter residues are three novel and highly fluorescent molecules. These are useful as inhibitors and as markers for trafficking of molecules in the cells compartments. Dr. Parry has recently reported the structure of the class II major histocompatibility complex DRA, DRB3 in complex with an integrin peptide (PDB code 2Q6W). This is the first structure from the DRB3 gene locus. The structure models at high resolution the molecular basis of severe blood diseases associated with pregnancy, neonates, blood transfusion, stem cell and tissue transplant.