Poster abstracts
Poster number 31 submitted by Will Higgins
Metadynamics-Based Prediction of Interaction Affinities with Contour
William T Higgins (Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43081)
Abstract:
Protein evolution does not occur at a fixed rate over time, but rather as a dynamic process influenced by physiological and genetic factors. Some protein sites are subject to higher degrees of evolutionary conservation than others, such as catalytic residues or residues involved in forming protein-protein interactions. To facilitate the exploration of these dynamic evolutionary processes, we have developed Contour, a Python-based molecular dynamics (MD) tool specifically tailored for biologists. Contour simplifies the MD workflow by allowing users to provide only an initial protein structure and desired simulation conditions by automating complex tasks that typically require specialized computational knowledge. Contour leverages pre-existing, widely validated tools such as Desmond and the Schrödinger software suite, creating an accessible yet powerful platform for simulation preparation, execution, and post-simulation analysis. One feature in Contour is the metadynamics functions, adapted from an established metadynamics-based dissociation free energy (DFE) methodology. This approach enables accurate predictions of dissociation constants (KD) for protein-protein interactions (PPIs) across a wide range of affinities (i.e., nM-µM), by simulating the dissociation process using user-defined collective variables. Specifically, Contour performs multiple independent simulations, systematically adding Gaussian energy potentials to drive dissociation, and calculates DFEs from averaged trajectories. The accessibility of Contour and its application in estimating binding affinities make it an invaluable tool for researchers studying evolutionary dynamics, protein interaction specificity, and molecular recognition processes. Ultimately, this offers biologically informed insights into protein evolution and function.
Keywords: Metadynamics, Protein Protein Interactions