Entropy-Enthalpy Compensations Fold Proteins in Precise Ways.

Jiacheng Li,Lin Yang,Hongchi Zhang,Xiaodong He,Chenchen Liao,Liping Shi,Chengyu Hou,Xiaoliang Ma,Lin Ye,Shuai Guo,Bing Zheng

doi:10.3390/ijms22179653

Abstract

Exploring the protein-folding problem has been a longstanding challenge in molecular biology and biophysics. Intramolecular hydrogen (H)-bonds play an extremely important role in stabilizing protein structures. To form these intramolecular H-bonds, nascent unfolded polypeptide chains need to escape from hydrogen bonding with surrounding polar water molecules under the solution conditions that require entropy-enthalpy compensations, according to the Gibbs free energy equation and the change in enthalpy. Here, by analyzing the spatial layout of the side-chains of amino acid residues in experimentally determined protein structures, we reveal a protein-folding mechanism based on the entropy-enthalpy compensations that initially driven by laterally hydrophobic collapse among the side-chains of adjacent residues in the sequences of unfolded protein chains. This hydrophobic collapse promotes the formation of the H-bonds within the polypeptide backbone structures through the entropy-enthalpy compensation mechanism, enabling secondary structures and tertiary structures to fold reproducibly following explicit physical folding codes and forces. The temperature dependence of protein folding is thus attributed to the environment dependence of the conformational Gibbs free energy equation. The folding codes and forces in the amino acid sequence that dictate the formation of β-strands and α-helices can be deciphered with great accuracy through evaluation of the hydrophobic interactions among neighboring side-chains of an unfolded polypeptide from a β-strand-like thermodynamic metastable state. The folding of protein quaternary structures is found to be guided by the entropy-enthalpy compensations in between the docking sites of protein subunits according to the Gibbs free energy equation that is verified by bioinformatics analyses of a dozen structures of dimers. Protein folding is therefore guided by multistage entropy-enthalpy compensations of the system of polypeptide chains and water molecules under the solution conditions.

Highlights

Introduction distributed under the terms andProteins are the building blocks of life on Earth and they perform a vast array of functions within organisms
At constant temperature and pressure, the change in Gibbs free energy is defined as ∆G = ∆H − T∆S, where ∆H represents the change in enthalpy, and ∆S represents the change in entropy
The hydrophobic interaction among the neighboring side-chains of the polypeptide chain and the thereby multistage entropy-enthalpy compensation mechanism drive the entire folding process throughout the developments of secondary, multi-domain, tertiary, and quaternary structures that can clearly explain the accuracy of protein folding in time sequence

Summary

Introduction

Introduction distributed under the terms andProteins are the building blocks of life on Earth and they perform a vast array of functions within organisms. The intrinsic biological functions of a protein are determined by its native three-dimensional conditions of the Creative Commons. (3D) structure that derives from the physical process of protein folding [1], by which means a polypeptide folds into its native characteristic and functional 3D structure in an spontaneous manner. Protein folding can be considered the most important mechanism, principle, and motivation for biological existence, functionalization, diversity, and evolution [2,3,4]. The protein-folding problem was brought to light over 60 years ago. Given the complexity of protein folding, the protein-folding problem has been summarized in three unanswered questions [1]: (i) What is the physical folding code in the amino acid sequence that dictates the particular native 3D structure? Given the complexity of protein folding, the protein-folding problem has been summarized in three unanswered questions [1]: (i) What is the physical folding code in the amino acid sequence that dictates the particular native 3D structure? (ii) What is the folding mechanism that enables proteins to fold so quickly? (iii) Is it possible to devise a computer algorithm to effectively predict a protein’s native structure from its amino acid sequence? A fourth essential question is: Why does protein folding highly depend on the solvent (water) [5]

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