Solvation Effects and Driving Forces for Protein Thermodynamic And Kinetic Cooperativity: How Adequate Is Native-Centric Topological Modeling?

TL;DR

This study evaluates the limitations of native-centric topological models in explaining protein folding thermodynamics and kinetics, emphasizing the need for additional energetic factors and solvent effects to accurately replicate experimental behaviors.

Contribution

It demonstrates that native-centric models alone are insufficient for two-state thermodynamics and kinetics, highlighting the importance of local conformational preferences and solvent effects.

Findings

Native-centric contact energies alone do not produce two-state thermodynamics.

Additional native biases are necessary for realistic thermodynamic modeling.

Models exhibit non-two-state kinetics with chevron rollovers and internal friction.

Abstract

What energetic and solvation effects underlie the remarkable two-state thermodynamics and folding/unfolding kinetics of small single-domain proteins? To address this question, we investigate the folding and unfolding of a hierarchy of continuum Langevin dynamics models of chymotrypsin inhibitor 2. We find that residue-based additive G\=o-like contact energies, although native-centric, are by themselves insufficient for proteinlike calorimetric two-state cooperativity. Further native biases by local conformational preferences are necessary for proteinlike thermodynamics. Kinetically, however, even models with both contact and local native-centric energies do not produce simple two-state chevron plots. Thus a model protein's thermodynamic cooperativity is not sufficient for simple two-state kinetics. The models tested appear to have increasing internal friction with increasing native stability, leading to chevron rollovers that typify kinetics that are commonly referred to as non-two-state. The free energy profiles of these models are found to be sensitive to the choice of native contacts and the presumed spatial ranges of the contact interactions. Motivated by explicit-water considerations, we explore recent treatments of solvent granularity that incorporate desolvation free energy barriers into effective implicit-solvent intraprotein interactions. This additional feature reduces both folding and unfolding rates vis-\`a-vis that of the corresponding models without desolvation barriers, but the kinetics remain non-two-state. Taken together, our observations suggest that interaction mechanisms