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
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
Andersen, Ole Juul; Risør, Michael Wulff; Poulsen, Emil Christian et al. (2017) Reactive Center Loop Insertion in ?-1-Antitrypsin Captured by Accelerated Molecular Dynamics Simulation. Biochemistry 56:634-646
Pang, Yui Tik; Miao, Yinglong; Wang, Yi et al. (2017) Gaussian Accelerated Molecular Dynamics in NAMD. J Chem Theory Comput 13:9-19
Chan, Albert H; Yi, Sung Wook; Weiner, Ethan M et al. (2017) NMR structure-based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors. Chem Biol Drug Des 90:327-344
Jaremko, Matt J; Lee, D John; Patel, Ashay et al. (2017) Manipulating Protein-Protein Interactions in Nonribosomal Peptide Synthetase Type II Peptidyl Carrier Proteins. Biochemistry 56:5269-5273
Miao, Yinglong; McCammon, J Andrew (2016) G-protein coupled receptors: advances in simulation and drug discovery. Curr Opin Struct Biol 41:83-89
Miao, Yinglong; Baudry, Jerome; Smith, Jeremy C et al. (2016) General trends of dihedral conformational transitions in a globular protein. Proteins 84:501-14
Miao, Yinglong; McCammon, J Andrew (2016) Unconstrained Enhanced Sampling for Free Energy Calculations of Biomolecules: A Review. Mol Simul 42:1046-1055
Miao, Yinglong; Goldfeld, Dahlia Anne; Moo, Ee Von et al. (2016) Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor. Proc Natl Acad Sci U S A 113:E5675-84
Wang, Nuo; McCammon, J Andrew (2016) Substrate channeling between the human dihydrofolate reductase and thymidylate synthase. Protein Sci 25:79-86

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