Molecular diffusion, often steered and accelerated by solute interactions, critically influences the outcomes of many biological processes. Diffusion is known to influence or control the kinetics of many enzymes, and the rates of action of such enzymes may be increased by several orders of magnitude by electrostatic attraction of charged substrates toward the enzyme active sites. Likewise, electrostatically steered diffusion greatly speeds the interaction of proteins with other proteins, with nucleic acids, and with macromolecular assemblages on membranes in a variety of processes essential for cytoskeletal remodeling, cargo transport, gene expression, and signal transduction. The broad objectives of the proposed work are to provide new computer simulation tools that will enable the detailed analysis of the role of molecular diffusion in biological processes at the subcellular and cellular levels, and the application of these tools to selected problems where close contact with experimental work is possible. More specifically, a new Brownian dynamics simulation package will be developed that will include many novel theoretical methods to increase the accuracy and scales of diffusional simulations. A unique, unified polar-apolar implicit solvation theory invented in the current grant period (the Variational Implicit Solvent Method) will be extended in a number of important directions to provide unprecedented accuracy in future Brownian dynamics and other simulations. A unique approach is proposed that will couple Brownian dynamics simulations for a proper stochastic treatment in critical domains with efficient continuum treatments elsewhere. Applications will be made to study signal transduction phenomena from molecular to cellular scales. The health relatedness of this work lies in the potential of diffusional simulations to reveal the detailed dynamics of molecular interactions within healthy cells and how these dynamics may be altered in pathological situations. This will provide a basis for future work in structure-based drug discovery, in which small molecules are used to modulate the dynamic processes within the cell.

Public Health Relevance

Diffusional interactions among small molecules and macromolecules such as proteins occur continuously in healthy cells, and are disrupted in various ways in diseased cells. In this work, computer simulation methods are being used to create a virtual microscope to observe these diffusional processes, and how they may be altered by external interventions such as the introduction of therapeutic agents. This will provide a basis for future work in structure-based drug discovery, in which small molecules are used to modulate the dynamic processes within the cell.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
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Preusch, Peter
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Miao, Yinglong; McCammon, J Andrew (2016) Graded activation and free energy landscapes of a muscarinic G-protein-coupled receptor. Proc Natl Acad Sci U S A 113:12162-12167
Miao, Yinglong; McCammon, J Andrew (2016) Unconstrained Enhanced Sampling for Free Energy Calculations of Biomolecules: A Review. Mol Simul 42:1046-1055
Wang, Nuo; McCammon, J Andrew (2016) Substrate channeling between the human dihydrofolate reductase and thymidylate synthase. Protein Sci 25:79-86
Kim, M Olivia; McCammon, J Andrew (2016) Computation of pH-dependent binding free energies. Biopolymers 105:43-9
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Cheng, Yuanhua; Rao, Vijay; Tu, An-Yue et al. (2015) Troponin I Mutations R146G and R21C Alter Cardiac Troponin Function, Contractile Properties, and Modulation by Protein Kinase A (PKA)-mediated Phosphorylation. J Biol Chem 290:27749-66
Kim, M Olivia; Blachly, Patrick G; McCammon, J Andrew (2015) Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria. PLoS Comput Biol 11:e1004341

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