Energetics of Protein Thermodynamic Cooperativity: Contributions of Local and Nonlocal Interactions

TL;DR

This study investigates how local and nonlocal interactions contribute to protein thermodynamic cooperativity using coarse-grained models, revealing that both interaction types are essential for cooperative folding behavior.

Contribution

It demonstrates that both local and nonlocal interactions are necessary for protein cooperativity, providing insights through continuum models and comparing with lattice models and experimental data.

Findings

Both local and nonlocal interactions are critical for thermodynamic cooperativity.

Weakening either local or nonlocal interactions reduces cooperativity.

The results align with experimental measures of protein folding behavior.

Abstract

The respective roles of local and nonlocal interactions in the thermodynamic cooperativity of proteins are investigated using continuum (off-lattice) native-centric G\=o-like models with a coarse-grained C$_\alpha$ chain representation. We study a series of models in which the (local) bond- and torsion-angle terms have different strengths relative to the (nonlocal) pairwise contact energy terms. Conformational distributions in these models are sampled by Langevin dynamics. Thermodynamic cooperativity is characterized by the experimental criteria requiring the van't Hoff to calorimetric enthalpy ratio $\Delta H_{\rm vH}/\Delta H_{\rm cal}\approx 1$ (the calorimetric criterion), as well as a two-state-like variation of the average radius of gyration upon denaturation. We find that both local and nonlocal interactions are critical for thermodynamic cooperativity. Chain models with either much weakened local conformational propensities or much weakened favorable nonlocal interactions are significantly less cooperative than chain models with both strong local propensities and strong favorable nonlocal interactions. These findings are compared with results from a recently proposed lattice model with a local-nonlocal coupling mechanism; their relationship with experimental measurements of protein cooperativity and chain compactness is discussed.