STRUCTURAL INSIGHTS INTO FOLDED, UNFOLDED AND NASCENT PROTEIN STATES USING ENSEMBLE SAMPLING AND CLUSTER EXPANSION

Abstract

Understanding non-native states of proteins (nascent, unfolded, and disordered) is important due to their implications in protein folding and human pathologies. Protein refolding is the closest model to study protein folding. Ensemble Modelling is used to generate denatured and disordered state ensembles of proteins by conformational sampling. This model demonstrates excellent agreement with experimental data and identifies native-like residual structures in the denatured state. Ensemble modelling provides the first all-atom model of denatured proteins and its residual structures. The nascent polypeptide structure in the ribosome tunnel is analysed with Delaunay triangulation and molecular dynamics simulations to investigate joint tunnel and polypeptide dynamics. The polypeptide decreases the tunnel volume and increases the surface area. Spatial threshold analysis shows increasing freedom towards the exit and accommodates folded conformations. Cluster Expansion is used to identify energetically interacting clusters of positions in protein structure. These clusters play important roles in protein stability and function.