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Theory and Modeling of Biomolecules and their Interactions

生物分子及其相互作用的理论和建模

基本信息

批准号：
10094219
负责人：
CHARLES L BROOKS
金额：
$ 83.16万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10094219
关键词：
Acids Actin-Binding Protein Address Area Big Data Biological Biomedical Research CREBBP gene Chemicals Collaborations Communities Complex Computer Simulation Computer software Computing Methodologies Development Docking Environment Enzymes Equilibrium Evolution Fibroblast Growth Factor Flavins Free Energy GTP-Binding Proteins Genetic Transcription Goals HRX protein Interleukins Ligand Binding Ligands MED25 gene Malignant Neoplasms Mediating Mediation Menin Methodology Methods Mixed Function Oxygenases Modeling Molecular Nucleic Acids Oncogenic Pharmaceutical Preparations Pharmacologic Substance Phosphotransferases Play Process Proteins Protocols documentation Research Role Signal Transduction Statistical Mechanics Statistical Methods Structure Technology Testing Thermodynamics Transcriptional Activation Work base cancer therapy design inhibitor/antagonist innovation insight models and simulation molecular dynamics novel protein protein interaction protonation receptor sensor simulation small molecule software development software infrastructure theories tool

项目摘要

Project Summary/Abstract The establishment of tools and methods from statistical mechanics and computer simulation technology to enable the exploration of biological molecules and their interactions plays a central role in discovery within biomedical research. This proposal represents a request for support of our ongoing efforts in this area and includes objectives to address challenges in the theory and modeling associated with these problems, as well as strategically chosen collaborations that will help elucidate important biomedical questions and provide crucial tests of the approaches we develop. Our proposed development efforts include the exploration of receptor-ligand interactions and the thermodynamics of ligand binding to biological receptors through the continued development and application of novel methods of free energy simulations to ligand binding thermodynamics, docking and receptor-ligand interaction modeling. The continued refinement, hardening and application of theoretical and computational methods of constant pH molecular dynamics to integrate the critical aspects of pH and protonation state changes in protein and nucleic acid receptors and their ligands in molecular simulations and modeling represents another challenge we will continue to address with the proposed work. Finally, software infrastructure, specifically the CHARMM macromolecular simulation package, provides the framework for advancing our methodological approaches and enabling the broader community to explore biomedically motivated questions via its wide usage and distribution. A component of our proposed efforts will be to continue the innovative implementation of methods and simulation approaches into this community standard software package. We will balance and drive our development efforts in the areas of free energy simulations, ligand – receptor docking and pH-mediated structure-function processes, important to a deeper mechanistic understanding of biomedically directed questions, through strategic collaborations with experimental colleagues in the areas of: transcriptional activation based on small amphipathic molecules targeting co-activators from the CREB binding protein (KIX) and the AciD domain of Med25; key cancer targets such as menin-MLL protein- protein interaction inhibition; inhibitors of acyl protein thioesterases, targeted in anti-cancer therapies for oncogenic HRas; enzyme redesign and substrate scope expansion to better understand the evolution of function of a novel Flavin-dependent hydroxylase in exploiting complex chemical transformations important in the development of pharmaceuticals; pH-regulated sensors in kinase signaling associated with the G-protein from the tetrameric Gai protein; the pH-modulated switch for myristoylated histactophilin, the actin binding protein that is structurally homologous with interleukin-1b and fibroblast growth factor. Finally, we will engage experts in the development of big data applications of molecular simulations and the design and execution of robust user APIs to work with us toward advancing objectives in software development for large multi-scale simulations of cellular environments and automated workflows, through CHARMM-GUI, for sophisticated simulation protocols.

项目总结/文摘