Exploring the Protein G Helix Free Energy Surface by Solute Tempering Metadynamics

TL;DR

This study combines metadynamics and solute tempering to efficiently explore the free-energy landscape of protein G's alpha-helix, reproducing experimental features and revealing insights into its conformational states.

Contribution

It introduces a combined computational approach that enhances sampling efficiency for protein free-energy landscapes, applicable to larger proteins.

Findings

The lowest energy conformation is a globular state with some beta-structure.

The alpha-helix is metastable, involving 65% of the chain.

The pi-helix and hydrophobic staple motifs are identified as stabilizing features.

Abstract

The free-energy landscape of the alpha-helix of protein G is studied by means of metadynamics coupled with a solute tempering algorithm. Metadynamics allows to overcome large energy barriers, whereas solute tempering improves the sampling with an affordable computational effort. From the sampled free-energy surface we are able to reproduce a number of experimental observations, such as the fact that the lowest minimum corresponds to a globular conformation displaying some degree of beta-structure, that the helical state is metastable and involves only 65% of the chain. The calculations also show that the system populates consistently a pi-helix state and that the hydrophobic staple motif is present only in the free-energy minimum associated with the helices, and contributes to their stabilization. The use of metadynamics coupled with solute tempering results then particularly suitable to provide the thermodynamics of a short peptide, and its computational efficiency is promising to deal with larger proteins.