Nonnative Energetic Frustrations in Protein Folding at Residual Level: A Simulation Study of Homologous Immunoglobulin-like β-Sandwich Proteins.

Yunxiang Sun,Dengming Ming,Feng Ding

doi:10.3390/ijms19051515

Abstract

Nonnative interactions cause energetic frustrations in protein folding and were found to dominate key events in folding intermediates. However, systematically characterizing energetic frustrations that are caused by nonnative intra-residue interactions at residual resolution is still lacking. Recently, we studied the folding of a set of homologous all-α proteins and found that nonnative-contact-based energetic frustrations are highly correlated to topology of the protein native-contact network. Here, we studied the folding of nine homologous immunoglobulin-like (Ig-like) β-sandwich proteins, and examined nonnative-contact-based energetic frustrations Gō-like model. Our calculations showed that nonnative-interaction-based energetic frustrations in β-sandwich proteins are much more complicated than those in all- proteins, and they exhibit highly heterogeneous effects on the folding of secondary structures. Further, the nonnative interactions introduced distinct correlations in the folding of different folding-patches of β-sandwich proteins. Taken together, a strong interplay might exist between nonnative-interaction energetic frustrations and the protein native-contact networks, which ensures that β-sandwich domains adopt a common folding mechanism.

Highlights

Most nascent polypeptide chains undergo a series of folding events before they acquire the compact biologically functioning three-dimensional (3D) conformations
The dynamics of intra-residue contacts defines the details of protein folding kinetics, which leads a protein to its native structure
Homotypic mutations exist in three structures: domain R23A has an additional mutation of T21K, domain N36I has T47S, A57V, I77V, and another hydrophilic-hydrophobic mutation Q1F, and domain Y94D has N55K, W98L

Summary

Introduction

Most nascent polypeptide chains undergo a series of folding events before they acquire the compact biologically functioning three-dimensional (3D) conformations. During protein folding, some residues come close to each other, and stay together and form the so-called native contacts in the native structures, while others only form transient contacts—called non-native contacts, which are separated in the final structures Both experimental data and theoretical simulations have suggested that native-contacts play essential roles in determining both the protein folding kinetics and the native structures [2,3,4,5]. Minimally frustrated models of protein folding were developed, where non-native intra-residue interactions are systematically suppressed [6,7,8,9]. According to the nucleation mechanism of protein folding, the formation of a few key native contacts in the polypeptide chain can start a series of down-hill like conformation changes towards the protein native states, without being trapped in any intermediate states at a local minimum

Methods

Results

Conclusion