Project: CryptoPocketSim. Understanding the mechanism of cryptic pocket formation at protein-protein interfaces.

Prace Call: 17th
ID: 2018184448, Leader: Francesco Gervasio
Affiliation: University College London, UK
Research Field: BiochemistryBioinformatics and Life sciences
Collaborators: Antonija Kuzmanic University College London UK
Resource Awarded: 20 Mil. core hours on Piz Daint

Abstract

The long-term aim of this project is to understand the mechanism of formation of “cryptic” pockets and allosteric regulation in relevant drug targets by means of enhanced-sampling simulations. “Cryptic” pockets, that is, sites on protein drug targets that only become apparent when a drug binds, offer an attractive opportunity for the development of drugs for difficult targets where classic drug-design strategies fail. However, due to their hidden nature, they have been in most cases discovered by chance. What is more, the molecular mechanisms by which cryptic pockets are formed, or even how common they are is still unclear. My group has pioneered the use of enhanced sampling simulations to discover cryptic pockets and described a previously unknown one in an anticancer target (FGFR). We also investigated the nature of cryptic sites in a number of pharmacological targets, such as the beta-lactamase TEM1 (a target for antimicrobial resistance). Building on that successful experience, we recently developed an effective Hamiltonian Replica Exchange-based approach (SWISH) and combined it with small molecular probes to sample cryptic pocket opening. Our initial results published in JACS attracted a lot of interest from both academia and industry. Thanks to our PRACE 15 allocation we were able to use a combination of SWISH and Metadynamics on Mare Nostrum to study more complex cases, such as the cryptic pocket forming at the protein-protein interface of the trimeric tumour necrosis factor alpha (TNFa). This revealed an interesting mechanism and allowed us to fine tune our algorithms. Here we propose to complete the study of TNFa and expand our investigation to the tumour necrosis factors super-family, an extremely promising target family for many complex diseases. This project is a continuation and expands on our successful PRACE 15 CryptoPocketSim project and will continue to benefit from a collaboration with a committed industrial partner.