Critical examination of the inherent-structure-landscape analysis of two-state folding proteins

TL;DR

This paper critically evaluates the inherent-structure-landscape approach for analyzing two-state folding proteins, demonstrating its qualitative accuracy but identifying inherent quantitative limitations regardless of sampling enhancements.

Contribution

It extends the ISL analysis to multiple proteins of different sizes, examining its limitations and validating its qualitative thermodynamic predictions.

Findings

ISL correctly describes thermodynamic functions qualitatively

Quantitative limitations of ISL are inherent and not fixed by sampling improvements

The approach works across different protein sizes and structures

Abstract

Recent studies attracted the attention on the inherent structure landscape (ISL) approach as a reduced description of proteins allowing to map their full thermodynamic properties. However, the analysis has been so far limited to a single topology of a two-state folding protein, and the simplifying assumptions of the method have not been examined. In this work, we construct the thermodynamics of four two-state folding proteins of different sizes and secondary structure by MD simulations using the ISL method, and critically examine possible limitations of the method. Our results show that the ISL approach correctly describes the thermodynamics function, such as the specific heat, on a qualitative level. Using both analytical and numerical methods, we show that some quantitative limitations cannot be overcome with enhanced sampling or the inclusion of harmonic corrections.