Probing the Energy Landscape of Intrinsically Disordered Proteins

• Grant number: 24/09560-3
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2024
• End date: September 30, 2026
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Vitor Barbanti Pereira Leite
• Grantee: Vitor Barbanti Pereira Leite
• Principal researcher abroad: Joan Shea
• Institution abroad: University of California, Santa Barbara (UC Santa Barbara) , United States
• Host Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil
• City of the host institution: São José do Rio Preto
• Associated researchers: Ana Paula Ribeiro Povinelli ; Ingrid Bernardes Santana Martins
• Associated research grant: 22/07231-7 - Plasticity and functional modulation of intrinsically disordered proteins, AP.TEM

Abstract

Understanding the relationships between protein structure, energetics, and function is crucial for elucidating biomolecular processes. This is particularly significant for intrinsically disordered proteins (IDPs), which lack a stable structure under physiological conditions. Due to their extreme malleability, IDPs engage in multiple protein interactions, and their dysfunctions, such as aggregation and fiber formation, are linked to various pathologies, including neurodegenerative diseases, diabetes, and cancer. The energy landscape theory, which emphasizes the importance of a statistical characterization of the energetic minima sampled by proteins during conformational transitions, has significantly advanced our comprehension of complex molecular systems. This project aims to study key IDPs using this theory.Our core strategy involves visualizing energy landscapes with a technique developed at UNESP, known as the Energy Landscape Visualization Method (ELViM). This method has shown great potential in detailing molecular mechanisms, and it is particularly suitable for studying IDPs as it surpasses one-dimensional representations and does not rely on reaction coordinates or native reference structures.We will focus on IDPs that have been studied by Shea's group using exhaustive enhanced sampling replica exchange molecular dynamics simulations}, particularly the tau protein and the RNA-binding protein TDP-43, which are crucial in numerous neurodegenerative diseases. Methodologically, the procedures to study these systems can be adapted to other relevant IDPs, an offer a new framework for studying IDP conformational transitions and assembly. (AU)