Atomistic characterisation of the impact of pathogenic mutations on the dynamics of intrinsically disordered regions of annexins aiming at the engineering of modulator proteins

• Grant number: 25/19500-0
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2026
• End date: January 31, 2027
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Luis Felipe Santos Mendes
• Grantee: Luis Felipe Santos Mendes
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• City of the host institution: São Carlos
• Associated research grant: 22/06006-0 - Elucidating the impact of functional protein "liquid" and "solid" condensates in the secretory pathway, AP.GR

Abstract

This project aims to investigate, at the atomistic level, the effects of pathological mutations in the Annexin A11 protein, which is associated with neurodegenerative diseases such as Amyotrophic Lateral Sclerosis and Parkinson's disease. The strategy involves characterizing the conformational and energetic space of the native protein and its mutant variants (P36R, G38R, D40G, D40Y), with a particular focus on the role of intrinsically disordered regions in aggregate formation. Based on this characterization, cutting-edge generative deep learning algorithms will be employed to propose and optimize engineered proteins capable of interacting with the affected regions and preventing aggregation. The stability of these interactions will be assessed through classical molecular dynamics simulations. The project will provide the fellow with direct exposure to state-of-the-art tools in computational structural biology and protein engineering, fostering critical thinking, scientific autonomy, and solid preparation for future enrollment in graduate programs. Moreover, it reinforces the importance of basic and applied research in proposing innovative therapeutic strategies for neurodegenerative diseases. (AU)