Carlos Simmerling of Stony Brook University (SBU) is supported by an award from the Chemical Theory, Models and Computational Methods program in the Chemistry Division to develop improved computational models of protein molecules. Proteins are the workhorses of biology. They perform more than 20,000 different chemical and mechanical functions in humans, and in all other living organisms. A major challenge in understanding the detailed mechanisms of biology is that proteins are not rigid objects. They move and twist in ways that are essential for their function. This is often where the crucial recognition between molecules takes place, as molecules adapt and pull on each other to confirm that they are interacting with the correct partner, much as two hands adapt during a handshake. These crucial motions can be studied via atomically-detailed computer simulations, using classical approximations to the underlying quantum mechanical forces, known as force fields. Force fields enable the accurate simulation of proteins and their interactions, studies that would otherwise be intractable, even on the largest supercomputers. In addition to fundamental biological studies, accurate force fields are essential for drug discovery and the design of novel nanoscale and biomimetic materials. Professor Simmerling, in collaboration with Qin Wu of Brookhaven National Laboratory, is performing a comprehensive, systematic, physics-based reshaping of one of the most important models used in molecular dynamics simulations of biophysical and biomolecular systems, the Amber force field. The goal of the project is to significantly improve the force field's accuracy and fidelity, while preserving its ability to simulate large biomolecular systems for long times. The newly-parameterized force field will be made freely available for download and use by the simulation community, for use within the most widely-used molecular dynamics simulation codes running on XSEDE supercomputers and small lab clusters. Outreach efforts for the project include regular research and recruitment trips to HBCU institutions, coordinated through the SBU Center for Inclusive Education, and the recruitment of undergraduates from underrepresented minorities to participate in the research.
The goal of this project is to systematically and consistently address several key limitations of existing protein classical force fields in order to improve their accuracy without dramatically increasing computational complexity. Current models work in some cases, but fail to agree with experiment in many others, including quantitative reproduction of amino-acid specific properties such as helical propensity. Professor Simmerling, in conjunction with collaborator Qin Wu of Brookhaven National Laboratory, is developing more accurate descriptions of the energy profiles for protein backbone structure and dynamics, with better sequence-dependent structure and dynamics, in order to extend and reparameterize the Amber force field. The project has three principal aims: (1) to improve the description of backbone energetics through fitting to multidimensional scans using high-level QM calculations in solution, (2) to expand the Amber force field parameter library to include non-standard amino acids encountered in biology and those frequently used as experimental probes, and (3) to begin to address longstanding weaknesses in the treatment of short-range van der Waals interactions, by taking advantage of recent advances in quantum mechanical energy decomposition methods to train alternate functional forms. These should improve the ability of the model to reproduce the known influence of side chain rotamer on backbone conformational preference. The new force field models are being validated, documented, and distributed via the widely-used Amber molecular dynamics (MD) simulation program, and can be independently downloaded for use in conjunction with other widely-used MD codes. Education and outreach is focused on recruiting and providing lab research experiences for students from underrepresented groups at SBU, and encouraging student interest in science and research through outreach trips to HBCU institutions.