[SCAN] Biophysical Constrains in the Evolution of Drug Resistance: the Case of Dihydrofolate Reductase

Seminar

Title: Biophysical Constrains in the Evolution of Drug Resistance: the Case of Dihydrofolate Reductase

Speaker: João Rodrigues, ITQB NOVA ALUMNI

Affiliation: Harvard University

Abstract:

Most proteins must adopt a specific tridimensional structure in order to function and fulfill their biological role in a living cell. Changes in the structure and function of proteins can occur throughout evolution, however, this process is believed to be highly constrained by the physical laws that dictate how proteins fold and by the biological requirements that must be met within complex cellular systems. As part of an effort to decipher some of the rules that control protein evolution, I will discuss the case of E. coli dihydrofolate reductase in the context of antibiotic resistance. Emphasis will be given to the biophysical trade-offs that impose barriers on the ability of a protein to escape drug inhibition. I will also present a model that bridges the biophysical properties of an enzyme with organismal fitness and that allows accurate predictions of mutant drug susceptibility levels. Finally, I will present our latest efforts to experimentally test models of protein evolution in controlled laboratory conditions using automation-based approaches.