Metamorphic proteins and how to find them

6^th February 2025, 14:00
Cesar A. Ramirez-Sarmiento
Millennium Institute for Integrative Biology and Pontificia Universidad Catolica de Chile

Abstract

A recently described class of metamorphic proteins is able to fold-switch between two structurally dissimilar native states to encode or regulate different biological functions. These proteins constitute a challenge for biophysical characterizations, for the identification of key residues driving the fold-switch, and for state-of-the-art protein structure predictions methods, such as AlphaFold2 (AF2). Using RfaH as a case study, we will showcase how the use of simplified structure-based models allows to understand their refolding pathways. We will also demonstrate how the use of local energetic frustration in MD simulations and across protein sequences aids in identifying key residues involved in its fold-switch behavior of RfaH, some of which we have experimentally validated. Finally, inspired by these results and by other works using subsampling of multiple sequence alignments (MSA) for protein structure prediction, we will show how a strategy of single position masking of the MSA in AlphaFold2 might aid in successfully exploring the conformational landscape of RfaH.