Modeling and Modulating macromolecular interactions
Thursday, January 16, 2020
3:30PM – 5PM
The protoplasmic revolution provided the blueprint for the networks of molecular interactions in the cell, however full understanding of how molecules interact comes only from three-dimensional structures. Despite recent progress in structure determination of individual proteins using X-ray or NMR, structures of complexes remains difficult to obtain. Additionally, modulating protein interactions for therapeutic purposes has become one of the modern frontiers of biomedical research. Thus, in silico modeling of macromolecular interactions has important motivations. My talk consists of two parts. First, I will describe the development of a physics based macromolecular docking method, which effectively uses geometry of the configuration space manifold. Specifically I will present application of generalized Fast Fourier Transforms on rotational group, for highly efficient global systematic search in the space of rigid body motions of one protein with respect to the other, and utilization of local optimization with exponential map parametrization of macromolecular interaction configurational manifold, for effective flexible protein refinement. I will demonstrate that the model is accurate enough not just to model the structure of the complex, but also provides biophysical insight in protein-protein association, which potentially enables mechanistic modeling of cellular crowding and therapeutics aggregation. The second part of the talk will focus on modeling protein small molecular interactions on the omics scale, building and expanding on ultra-fast algorithms described above. I will describe ongoing drug discovery and biological applications, including studying the kinome-wide possibility of targeting kinase allosteric sites with small molecules, and organism scale modeling of 3D structures of protein-metabolite interactions.
Dima Kozakov received a B.S. and M.S. in Applied Mathematics and Physics at the Moscow Institute of Physics and Technology, and PhD in Biomedical Engineering at Boston University. Currently he is Associate Professor in the Department of Applied Mathematics at Stony Brook University, and also Affiliate Member at Laufer Center for Physical and Quantitative Biology, Institute of Chemical Biology & Drug Discovery, and Institute of Advance Computational Sciences. Dr. Kozakov research focuses on the development of mathematically elegant, computationally efficient and physically accurate algorithms for modeling of biological macromolecules with emphasis on molecular interactions and drug design. Dr. Kozakov’s protein ligand docking approaches are consistently top performers in National Institute of Health (NIH) sponsored international competition D3R. His protein-protein docking method ClusPro has been consistently the best automatic server in the worldwide blind protein docking experiment CAPRI. Currently ClusPro has more than 20,000 users, with more than 200,000 jobs run in the last few years. The protein docking tools developed by Dr. Kozakov are licensed by Schrodinger, the largest pharmaceutical software vendor in the world, and are used by most major pharmaceutical companies worldwide. His research has been funded by the National Institute of Health, National Science Foundation, and Binational (US-Israel) Science Foundation.