Development and Application of Ensemble Reweighting Methods for Studies of Proteins Thermodynamics in the Presence of Cosolvents

• Grant number: 24/21000-3
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2025
• End date: August 31, 2029
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Physical-Chemistry
• Principal Investigator: Leandro Martinez
• Grantee: Lucas Verona de Araujo
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 13/08293-7 - CCES - Center for Computational Engineering and Sciences, AP.CEPID

Abstract

Understanding how cosolvents affect the protein folding equilibrium is a difficult challenge due a complex equilibrium of intermolecular interactions in the medium. Molecular dynamics simulations, combined with experiments, have aided in this investigation by revealing the main interactions between solvent, cosolvent, and protein, leading to the proposal of direct and indirect mechanisms for the modulation of protein folding. However, performing simulations that involve changes in mixture composition, protein mutations, or alchemical transformations in interactions reveals only few microscopic insights regarding individual contributions of interactions to the global structural modulation. Besides, simulating these systems leads to additional computational efforts. To address this issue, in this project we propose the development of an ensemble rewight methodology to unravel these contributions using a reduced number of simulations. We will simulate helical peptides and the HEWL protein in cosolvent solutions, characterizing the solvation of these biomolecules by the components of the mixtures and perturbing the main intermolecular interactions observed in the minimum-distance distribution functions. In doing so, we will evaluate how structural properties of proteins and macroscopic properties of the system rely on each observed interaction. Therefore, we expect to develop a fast and versatile method that provides new theoretical insights and deepens previously discussed aspects in the literature regarding the effects of cosolvent on protein structure. (AU)