Theory and Modeling of Biomolecules and their Interactions - Equipment Supplement

项目总结/文摘

Project Summary/Abstract The establishment of tools from statistical mechanics and computer simulation that enable the exploration of biological molecules and their interactions are central to discovery within biomedical research. This proposal supports ongoing efforts in this area, addressing challenges in theory and modeling, as well as strategically chosen collaborations on important biomedical questions that provide crucial tests of the approaches. Our development efforts include the exploration of receptor-ligand interactions and the thermodynamics of ligand binding to biological receptors through the development and application of novel methods of free energy simulations, docking and receptor-ligand interaction modeling. The continued refinement, hardening and application of methods of constant pH molecular dynamics to integrate the critical aspects of pH and protonation state changes in biomolecules and their ligands in molecular simulations and modeling is also part of ongoing work. Finally, software infrastructure, specifically the CHARMM 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. We will 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 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; enzyme redesign and substrate scope expansion to better understand the evolution of function of a novel Flavin-dependent hydroxylase for 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, an actin binding protein homolog with interleukin-1b and fibroblast growth factor. Finally, we will engage developers of big data applications of molecular simulations and the design and execution of robust user APIs to work with us toward advancing software development for large multi-scale simulations of cellular environments and automated workflows, through CHARMM-GUI, for simulation protocols. This requested supplement provides a critical update to the computational infrastructure needed for the developments and applications proposed as part of our R35 award. We have made significant efforts to map computational algorithms onto accelerated computing platforms (GPUs) and the proposed instrumentation will enable access to the latest of these platforms, replacing standard CPU and aging GPU platforms that are beyond their useful lifespan, thus facilitating the productivity of algorithm development and key biomedical applications.