Computer Simulation of Substrate Recognition: Folded protein versus IDP as Case Study
Prof. Jagannath Mondal
Tata Institute of Fundamental Research Hyderabad, India
The seminar will begin by presenting our group’s efforts to elucidate the mechanistic basis of substrate recognition by the ubiquitous metalloenzyme Cytochrome P450cam through atomistic MD simulations. We will demonstrate how a substrate like camphor navigates the conformational heterogeneity inherent in Cytochrome P450cam. Our simulations reveal that camphor recognizes the closed conformation of the protein via an induced fit pathway. In contrast, the open conformation of the protein allows for multi-substrate binding at three distinct, yet allosterically linked sites. Our identification of this so-called '3-site' state helps reconcile previous NMR-based pseudo-contact shift measurements of P450cam.
In the second part of the seminar, we will explore small-molecule binding to the intrinsically disordered protein (IDP) alpha-synuclein. We will present an integrative, machine learning-based approach that, in combination with a Markov State model, identifies key ligand-bound states of this IDP.