Abstract
Proteins exert their function by binding to other partners, interacting with other proteins and/or ligands. Protein-protein interactions (PPIs) occur on specific protein surface areas, where few residues (hot spots) largely contribute to binding free energy; their mutations may affect pathways, causing diseases. Autism spectrum disorder (ASD), a major neurodevelopmental disorder, presents molecular mechanisms still unclear. To investigate them, we are designing a protocol to assess the biophysical impact of genetic mutations in PPI networks where autism risk converges. Though no single biological process leads to ASD, studying synaptic mechanisms microscopically may improve our understanding. Our protocol integrates bioinformatic/genetic data (30,000 complexes) from UK/USA collaborators with our molecular studies. Hot spots will be characterized via machine learning (Germany). Results will support: 1) molecular dynamics simulations, 2) variant effects in PPI hubs, 3) in vitro studies. Achieved results The University of Bologna research unit provided the computational infrastructure and expertise required for the development of the automated pipeline for building protein complexes in both their wild-type and mutant forms. This activity required a considerable computational effort, as it involved testing and adapting computational procedures to meet the requirements of a flexible and user-friendly platform. The first step was devoted to the development of an effective procedure for mapping the mutations of interest onto the correct isoform of the protein under investigation. This represents extremely valuable information, since the functional properties of different isoforms of the same protein may differ. Subsequently, the development focused on the component of the platform dedicated to the construction of structural models, whenever possible, of the target protein in its wild-type form and of its variants. The use of the pipeline is not restricted to synaptic proteins but is fully general and applicable to any protein. Finally, a protein–protein docking procedure was implemented to automate the use of three different freely available software packages, enabling the calculation of quaternary protein complexes involving wild-type proteins and their corresponding mutants, when applicable. Publication currently under submission: S. Albani, S. Xie, A. Giorgetti, F. Musiani, Monviso 2.0: A Flexible Software Environment for Protein Modelling and Docking.
Project details
Unibo Team Leader: Francesco Musiani
Unibo involved Department/s:
Dipartimento di Farmacia e Biotecnologie
Coordinator:
Università degli Studi di CAGLIARI(Italy)
Total Unibo Contribution: Euro (EUR) 46.047,00
Project Duration in months: 24
Start Date:
28/09/2023
End Date:
28/02/2026
