Variational theory for site resolved protein folding free energy surfaces

TL;DR

This paper introduces a microscopic variational approach to analyze the free energy landscape of fast-folding proteins at the residue level, validated on lambda-repressor and aligned with mutagenesis data.

Contribution

It develops a novel variational method that resolves protein folding free energy surfaces at the residue level using local order parameters.

Findings

Native structure formation is well described by the capillarity approximation.

The free energy profile aligns with experimental mutagenesis data.

Local folding topology introduces fine structure in the free energy landscape.

Abstract

We present a microscopic variational theory for the free energy surface of a fast folding protein that allows folding kinetics to be resolved to the residue level using Debye-Waller factors as local order parameters. We apply the method to lambda-repressor and compare with site directed mutagenesis experiments. The formation of native structure and the free energy profile along the folding route are shown to be well described by the capillarity approximation but with some fine structure due to local folding topology.