Professor Lars Schäfer, Centre for Theoretical Chemistry, University of Bochum, Germany

Predicting Protein Complexes from All-Atom MD Simulations: The Rope Pulling Game between Tapasin and MHC I

Protein complexes are crucial for many cellular processes, yet often very little is known about their structural organization. Due to the large system sizes and time scales involved in typical protein-protein association events, theoretical approaches employed approximations such as treating the proteins as rigid bodies, describing the systems at a coarse-grained representation, or modeling the solvent as a dielectric continuum, all of which can affect the accuracy of the in silico predictions. All-atom MD simulations can overcome these limitations but were up to now considered computationally too demanding for describing protein-protein association in most cases.

Enabled by the use of parallel supercomputers and GPU computing, we employed all-atom MD simulations in explicit solvent to study protein-protein association on a multi-microsecond time scale. As a challenging test case and prime example for a protein complex, we simulated the association between major histocompatibility complex class I (MHC I) molecules and tapasin. MHC I molecules present peptide epitopes to cytotoxic T cells and hence are key players in the mammalian adaptive immune response. Due to the lack of high-resolution structures of the protein complex, the molecular events during peptide loading onto MHC I molecules were not well understood. The MHC I–tapasin complex obtained from our simulations provides the molecular basis for the differential binding of tapasin to peptide-loaded vs. -free MHC I. Furthermore, our simulations reveal the atomic details of the peptide editing mechanism, i.e., the loading of MHC I molecules with high-affinity peptides. Our simulations show that tapasin not only acts as a chaperone that stabilizes MHC I, it also catalyzes the exchange of abundant low-affinity peptides against high-affinity, immunodominant antigens according to an intriguing molecular rope-pulling mechanism.