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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031749-32
Application #
8505011
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter C
Project Start
1983-06-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
32
Fiscal Year
2013
Total Cost
$342,422
Indirect Cost
$121,505
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Guan, W; Cheng, X; Huang, J et al. (2018) RPYFMM: Parallel Adaptive Fast Multipole Method for Rotne-Prager-Yamakawa Tensor in Biomolecular Hydrodynamics Simulations. Comput Phys Commun 227:99-108
Jurrus, Elizabeth; Engel, Dave; Star, Keith et al. (2018) Improvements to the APBS biomolecular solvation software suite. Protein Sci 27:112-128
Huang, Yu-Ming M; Huber, Gary A; Wang, Nuo et al. (2018) Brownian dynamic study of an enzyme metabolon in the TCA cycle: Substrate kinetics and channeling. Protein Sci 27:463-471
Caliman, Alisha D; Miao, Yinglong; McCammon, James A (2018) Mapping the allosteric sites of the A2A adenosine receptor. Chem Biol Drug Des 91:5-16
Utesch, Tillmann; de Miguel Catalina, Alejandra; Schattenberg, Caspar et al. (2018) A Computational Modeling Approach Predicts Interaction of the Antifungal Protein AFP from Aspergillus giganteus with Fungal Membranes via Its ?-Core Motif. mSphere 3:
Zhang, Jingbo; Wang, Nuo; Miao, Yinglong et al. (2018) Identification of SLAC1 anion channel residues required for CO2/bicarbonate sensing and regulation of stomatal movements. Proc Natl Acad Sci U S A 115:11129-11137
Miao, Yinglong; McCammon, J Andrew (2018) Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor. Proc Natl Acad Sci U S A 115:3036-3041
Palermo, Giulia; Chen, Janice S; Ricci, Clarisse G et al. (2018) Key role of the REC lobe during CRISPR-Cas9 activation by 'sensing', 'regulating', and 'locking' the catalytic HNH domain. Q Rev Biophys 51:
Ricci, Clarisse G; Li, Bo; Cheng, Li-Tien et al. (2017) ""Martinizing"" the Variational Implicit Solvent Method (VISM): Solvation Free Energy for Coarse-Grained Proteins. J Phys Chem B 121:6538-6548
Dick, Benjamin L; Patel, Ashay; McCammon, J Andrew et al. (2017) Effect of donor atom identity on metal-binding pharmacophore coordination. J Biol Inorg Chem 22:605-613

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