Interplay between Secondary and Tertiary Structure Formation in Protein Folding Cooperativity

TL;DR

This study uses microcanonical analysis and molecular dynamics simulations to explore how secondary and tertiary structures influence the cooperative nature of protein folding transitions, revealing different folding behaviors in peptides.

Contribution

It demonstrates the effectiveness of microcanonical analysis combined with simulations to characterize protein folding transitions and elucidates the role of secondary and tertiary interactions in folding cooperativity.

Findings

Short helix exhibits two-state folding behavior.

Longer helix shows downhill folding transition.

Interplay between secondary and tertiary structures influences transition nature.

Abstract

Protein folding cooperativity is defined by the nature of the finite-size thermodynamic transition exhibited upon folding: two-state transitions show a free energy barrier between the folded and unfolded ensembles, while downhill folding is barrierless. A microcanonical analysis, where the energy is the natural variable, has shown better suited to unambiguously characterize the nature of the transition compared to its canonical counterpart. Replica exchange molecular dynamics simulations of a high resolution coarse-grained model allow for the accurate evaluation of the density of states, in order to extract precise thermodynamic information, and measure its impact on structural features. The method is applied to three helical peptides: a short helix shows sharp features of a two-state folder, while a longer helix and a three-helix bundle exhibit downhill and two-state transitions, respectively. Extending the results of lattice simulations and theoretical models, we find that it is the interplay between secondary structure and the loss of non-native tertiary contacts which determines the nature of the transition.