Entropy-Enthalpy Compensations Fold Proteins in Precise Ways

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.

SARS-CoV-2 Variants, RBD Mutations, Binding Affinity, and Antibody Escape

“…The folding of protein quaternary structures is found to be guided by the entropy-enthalpy compensations between the binding sites of protein subunits, according to the Gibbs free energy equation that is verified by the bioinformatic analyses of a dozen structures of dimers [50]. More specifically, entropy increments caused by hydrophobic surface areas collapse in between protein subunits, thus compensating for the increment of enthalpy caused by H-bond formation between the protein subunits [50]. where T is the temperature, S is the entropy, and H is the enthalpy.…”

“…The folding of protein quaternary structures is found to be guided by the entropy-enthalpy compensations between the binding sites of protein subunits, according to the Gibbs free energy equation that is verified by the bioinformatic analyses of a dozen structures of dimers [50]. More specifically, entropy increments caused by hydrophobic surface areas collapse in between protein subunits, thus compensating for the increment of enthalpy caused by H-bond formation between the protein subunits [50]. At the interface of a protein-protein complex, interactions among the surface areas of proteins can be classified into four types: hydrophobic-hydrophobic (Ho-Ho) interaction, hydrophobic-hydrophilic (Ho-Hi) interaction, attractive dipole-dipole (ADD) interaction, and repulsive dipole-dipole (RDD) interaction.…”

“…Entropy-enthalpy compensation should thus be considered a key mechanism that governs protein-protein docking processes. Note that the hydrophilicity of proteins at the binding site is normally expressed by CO or NH groups at the ends of hydrophilic side chains or the main chain [50]. Therefore, the attractive dipole-dipole interaction can be considered the hydrogen bonding between the CO groups and NH groups of the protein chains (see Figure 1c).…”

Modeling of the thermal properties of SARS-CoV-2 S-protein

“…The averaged potential energy, and entropy increase with rising temperature while the decreases. The increasing entropy contributes to the S-protein thermal unfolding ( Fitter, 2003 ; Dagan et al, 2013 ; Cui et al, 2014 ; Li et al, 2021 ). The decrease shows that the contribution of atomic interactions to decreases with increasing temperature, and the total kinetic energy fluctuations increase faster than that of the total potential energy ( Umirzakov, 2020 ).…”

Light, Water, and Melatonin: The Synergistic Regulation of Phase Separation in Dementia

“…This hypothesis remained largely controversial [ 162 , 163 ] until support from experimental evidence on protein hydration shells was published. When the original clathrate water hydration shell used by Kauzmann in 1959 was replaced by a dynamic one formed by van der Waals (vdW) attraction [ 164 ], it became clear that the structural differences between water molecules in hydration shells and bulk [ 165 ] contributed to changes in free energy produced in vdW attraction interactions that favored protein folding [ 166 , 167 ]. Furthermore, the fact that the addition of salt can tune the hydrophobic effect by breaking hydrogen bonds in hydration shells [ 168 ] and rearrange the hydrogen-bonding environment in interfacial waters [ 169 ], provides additional support for the role of dehydration in the formation of pathogenic amyloid fibrils.…”