Free Energies in Biomolecular Systems: Theoretical Development and Application of Computational Approaches

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The objective of this project, jointly funded by Molecular Biophysics in the Division of Molecular and Cellular Biosciences and the Theoretical and Computational Chemistry Program in the Chemistry Division, is to extend current theoretical and computational approaches used in the modeling of biomolecular systems and to develop and test protocols that will provide increased accuracy and reliability in estimating free energies while remaining computationally tractable. Molecular recognition phenomena involving the association of ligands to macromolecules with high affinity and specificity play a key role in biology and is a problem of central importance in computational biophysics. In principle, molecular dynamics (MD) simulations free energy perturbation (FEP) methods based on atomic models are arguably the most powerful and promising approaches to address such questions. Test calculations have shown that MD/FEP is much more reliable than simpler scoring schemes to compute relative binding affinities in important biological systems and that it can naturally handle the influence of dynamic flexibility. However, despite the outstanding developments in simulation methodologies, carrying out MD/FEP calculations of large macromolecular assemblies surrounded by explicit solvent molecules often remain prohibitive. For this reason, it is necessary to seek ways to decrease the computational cost of MD/FEP calculations while keeping them accurate. Although the fundamental microscopic interactions giving rise to molecular recognition are relatively well-understood, designing computational schemes to accurately calculate binding free energies remains very challenging. The goal of this research is to advance the fundamental knowledge in the theoretical and computational methodologies used to estimate free energies in biological systems. The education and training of highly qualified personnel is an intrinsic component of this project. The innovative theoretical developments will be implemented and primarily implemented and tested by graduate students and postdoctoral fellows. To further broaden the impact of this work, the PI has developed collaboration with Themis Lazaridis and Marilyn Gunner from the Chemistry Department at CCNY, to supervise research projects by undergraduate students from CCNY (a university with a wide diversity of ethnic groups located in Harlem). The PI's laboratory participates in the Tri-Institutional Weill Cornell - Rockefeller - Sloan-Kettering Gateways to the Laboratory Program, which trains underrepresented minority students to become successful MD-PhD applicants.