Molecular Dynamics

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Project Summary: Core C – Molecular Dynamics (MD) Core This P01 project explores several novel concepts and hypotheses regarding the role of mechanical force for the T-cell receptor (TCR) repertoire selection, antigen recognition, and signal generation. Core C carries out computer simulations that are necessary to elucidate the mechanisms at the atomistic level. Supported by our preliminary experimental and computational data, the key scientific premise of Core C is that pre-TCR (pT - ) and TCR function not as static structures, but by undergoing dynamic conformational motion. In particular, we have found that load can control the relative motion between different domains of TCR, which in turn affect the geometry of the antigenic peptide-loaded major histocompatibility complex (pMHC) binding interface. The novel mechanism will be further tested and refined through collaboration with experimental projects. Our analyses include: exhaustive monitoring of intra- and inter-molecular contact dynamics, conformational entropy calcu- lation, and identifying mechanically responsive domain motion. To test whether the proposed load-response mechanism is specific for TCR , we will carry out comparative studies of TCR that is functionally different from TCR and is less responsive to load. Using the computational approaches developed for TCR , we will investigate the effect of load on pT - . Preliminary simulation using our newly discovered x-ray structure rep- resenting a preTCR-MHC complex indicates that the binding interface between a peptide-free MHC and TCR is highly dynamic and mobile. We posit that a bound antigenic peptide and load will stabilize the interface into a configuration amenable to the repertoire selection at the pT - stage. Simulations in Core C will be developed through strong feedback loops established with individual projects, utilizing data from optical tweezers (Project 1 and 2), transcriptome (Project 1 for TCR and Project 2 for pT - ), and NMR (Project 3). Furthermore, in col- laboration with Core B (Protein Design), Core C will provide simulation-based design of mutants and chimeras that will be experimentally tested. Simulations will be performed on structures available in Protein Data Bank as well as new structures of TCR and pT - , individually or complexed with pMHC, that will be solved in this P01 project. We have access to several supercomputers that are sufficient for performing simulations as needed.