Executive Summary : | Intrinsically disordered proteins (IDP) are a crucial part of the biological proteome and have significant functional and biochemical relevance. However, they often display a fuzzy ensemble, making it difficult to establish a structure-function relationship through conventional experiments. This proposal aims to use a multiscale computer simulation framework to investigate the key monomeric conformational sub-ensemble and its possible aggregation. The core of the investigation will be a set of functionally important IDPs, including alpha-synuclein, Abeta40, Ash1, and sic1. The first phase will involve demultiplexing the conformational landscape of the monomeric IDPs using a novel Markov state model. The conformational sub-ensemble will be investigated for potential modulation in the presence of inert crowding agents, phosphorylation, and drug-like small molecules. The second phase will involve developing a coarse-grained model of IDPs based on atomistic simulation data. This model will be computationally simulated to investigate self-aggregation and liquid-liquid phase separation. The proposal aims to develop unique computational skills in PhD students in natural sciences and stimulate new experiments. |