Folding and Stabilization of Native-Sequence-Reversed Proteins

TL;DR

This study explores how reversed native protein sequences can fold into native-like structures, revealing size and core flexibility as key factors, and proposes mutational strategies to stabilize certain reverse sequences.

Contribution

It provides new insights into protein sequence-structure relationships by systematically analyzing reverse sequences across different protein types and proposing stabilization methods.

Findings

Reverse sequences can fold into native-like structures depending on size and core flexibility.

Mutational strategies can stabilize reverse sequences that initially fail to fold.

The study offers new perspectives for protein design and structure prediction.

Abstract

Though the problem of sequence-reversed protein folding is largely unexplored, one might speculate that reversed native protein sequences should be significantly more foldable than purely random heteropolymer sequences. In this article, we investigate how the reverse-sequences of native proteins might fold by examining a series of small proteins of increasing structural complexity ({\alpha}-helix, \b{eta}-hairpin, {\alpha}-helix bundle, and {\alpha}/\b{eta}-protein). Employing a tandem protein structure prediction algorithmic and molecular dynamics simulation approach, we find that the ability of reverse sequences to adopt native-like folds is strongly in influenced by protein size and the flexibility of the native hydrophobic core. For \b{eta}-hairpins with reverse-sequences that fail to fold, we employ a simple mutational strategy for guiding stable hairpin formation that involves the insertion of amino acids into the \b{eta}-turn region. This systematic look at reverse sequence duality sheds new light on the problem of protein sequence-structure mapping and may serve to inspire new protein design and protein structure prediction protocols.