This project develops a conceptually novel theory and robust computational technologies to investigate biomolecular interactions in aqueous solutions. Such interactions influence significantly protein folding, molecular recognition, and many other biological processes. One of the crucial properties of such interactions is the capillarity evaporation or dewetting that can affect critically the solvation free energy and biomolecular structures. The goal of this project is to better understand such hydrophobic interactions in biomolecular systems and to create a state-of-the-art computational program for molecular recognition. The new variational model couples all the dispersive, non-polar, and polar interactions to local geometry in a free-energy functional. This theoretical model and the level-set numerical method can well describe the hydrophobic interaction and complex free-energy landscapes of biomolecular systems that are generally not correctly captured in established implicit-solvent models. Sophisticated numerical methods for electrostatics are developed to couple with the level-set method. Further model refinement to include solute molecular mechanics and stochastic effects can lead to a new computer program for molecular recognition that will significantly improve the existing ones whose unsatisfactory performances have been widely recognized. The success of the project will reduce the high cost for experiments and speed up the process of drug discovery. The natural collaborations among mathematics, biosciences, and pharmaceutical industry in the proposed research make it convenient to transform the mathematical research into the life-saving reality. This highly interdisciplinary project brings exciting opportunities for students and postdoctoral researchers to receive training in mathematical bioscientific research and to gain experience of working in biomedical industry. The project also provides material for an urgently needed course on mathematical and computational molecular biology.

Public Health Relevance

One of the central objectives of computer-aided drug design is to dock efficiently and accurately small molecules to a target, large biomolecule in solution. This project provides a sophisticated way of such docking, and hence a better drug design program.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM096188-03
Application #
8286989
Study Section
Special Emphasis Panel (ZGM1-CBCB-5 (BM))
Program Officer
Preusch, Peter C
Project Start
2010-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$289,189
Indirect Cost
$68,453
Name
University of California San Diego
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Sun, Hui; Zhou, Shenggao; Moore, David K et al. (2016) Numerical Treatment of Stokes Solvent Flow and Solute-Solvent Interfacial Dynamics for Nonpolar Molecules. J Sci Comput 67:705-723
Li, B O; Wen, Jiayi; Zhou, Shenggao (2016) MEAN-FIELD THEORY AND COMPUTATION OF ELECTROSTATICS WITH IONIC CONCENTRATION DEPENDENT DIELECTRICS. Commun Math Sci 14:249-271
Zhou, Shenggao; Sun, Hui; Cheng, Li-Tien et al. (2016) Stochastic level-set variational implicit-solvent approach to solute-solvent interfacial fluctuations. J Chem Phys 145:054114
Zhou, Shenggao; Cheng, Li-Tien; Sun, Hui et al. (2015) LS-VISM: A software package for analysis of biomolecular solvation. J Comput Chem 36:1047-59
Li, B O; Sun, Hui; Zhou, Shenggao (2015) STABILITY OF A CYLINDRICAL SOLUTE-SOLVENT INTERFACE: EFFECT OF GEOMETRY, ELECTROSTATICS, AND HYDRODYNAMICS. SIAM J Appl Math 75:907-928
Sun, Hui; Wen, Jiayi; Zhao, Yanxiang et al. (2015) A self-consistent phase-field approach to implicit solvation of charged molecules with Poisson-Boltzmann electrostatics. J Chem Phys 143:243110
Hohn, Maryann E; Li, Bo; Yang, Weihua (2015) Analysis of Coupled Reaction-Diffusion Equations for RNA Interactions. J Math Anal Appl 425:212-233
Guo, Zuojun; Li, Bo; Cheng, Li-Tien et al. (2015) Identification of protein-ligand binding sites by the level-set variational implicit-solvent approach. J Chem Theory Comput 11:753-65
Li, B O; Liu, Yuan (2015) DIFFUSED SOLUTE-SOLVENT INTERFACE WITH POISSON-BOLTZMANN ELECTROSTATICS: FREE-ENERGY VARIATION AND SHARP-INTERFACE LIMIT. SIAM J Appl Math 75:2072-2092
Banham, Timothy; Li, Bo; Zhao, Yanxiang (2014) Pattern formation by phase-field relaxation of bending energy with fixed surface area and volume. Phys Rev E Stat Nonlin Soft Matter Phys 90:033308

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