Binding-and-Folding Recognition of an Intrinsically Disordered Protein Using Online Learning Molecular Dynamics.

• DOI: 10.48550/arxiv.2302.10348
• Publication Date: 2023-06-21
• Authors: Herrera-Nieto, Pablo; Pérez, Adrià; De Fabritiis, Gianni
• Keywords: 0301 basic medicine; FOS: Computer and information sciences; Computer Science - Machine Learning; Protein Folding; FOS: Physical sciences; Biomolecules (q-bio.BM); Molecular Dynamics Simulation; Computational Physics (physics.comp-ph); Machine Learning (cs.LG); Intrinsically Disordered Proteins; Education, Distance; 03 medical and health sciences; Quantitative Biology - Biomolecules; FOS: Biological sciences; Physics - Computational Physics; Protein Binding

Intrinsically disordered proteins participate in many biological processes by folding upon binding with other proteins. However, coupled folding and binding processes are not well understood from an atomistic point of view. One of the main questions is whether folding occurs prior to or after binding. Here we use a novel unbiased high-throughput adaptive sampling approach to reconstruct the binding and folding between the disordered transactivation domain of \mbox{c-Myb} and the KIX domain of the CREB-binding protein. The reconstructed long-term dynamical process highlights the binding of a short stretch of amino acids on \mbox{c-Myb} as a folded $α$-helix. Leucine residues, specially Leu298 to Leu302, establish initial native contacts that prime the binding and folding of the rest of the peptide, with a mixture of conformational selection on the N-terminal region with an induced fit of the C-terminal.