Single Molecule Thermodynamics Hypothesis of Protein Folding and Drug Design

Fang, Yi

doi:10.4236/jbm.2019.711015

Cited by 2 publications

(1 citation statement)

References 12 publications

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“…This is an explanation of denaturation in different temperature, the stable conformations in environment E will be different from X U . In general, this is summarized as the single molecule thermodynamic hypothesis [13]:…”

Section: Introductionmentioning

confidence: 99%

Entropy-Enthalpy Compensations Fold Proteins in Precise Ways

Hou

et al. 2021

IJMS

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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.

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Section: Introductionmentioning

confidence: 99%

Entropy-Enthalpy Compensations Fold Proteins in Precise Ways

Hou

et al. 2021

IJMS

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Applications of a Single Molecule Theory of Protein Dynamics

2024

JBM

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A single molecule theory for protein dynamics has been developed since 2012. It consists of the concepts of conformational Gibbs free energy function (CGF) and single molecule thermodynamic hypothesis (STH) that claims that all stable conformations are (local or global) minimizers of CGF. These are enough to give a unified explanations and mechanisms to many aspects of protein dynamics such as protein folding; allostery; denaturation; and intrinsically disordered proteins. Formulas of CGF in water environment had been derived via quantum statistics. Applications of them to soluble proteins are: docking Gibbs free energy difference formula and a practical way to search better docking site; single molecule binding affinity; predicting and explaining why structures of a monomeric globular protein looks like a globule and is tightly packed with a hydrophobic core; a representation of the hydrophobic effect; and a wholistic view to structures of water soluble proteins.

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Single Molecule Thermodynamics Hypothesis of Protein Folding and Drug Design

Abstract: A single molecule view of protein folding leads to the concept of conformational Gibbs free energy function (; ,) G X E U , where the variable X is a conformation of a protein U. U and environments E (solvent, temperature, pressure, other particles in solvent, etc.

Cited by 2 publications

References 12 publications

Entropy-Enthalpy Compensations Fold Proteins in Precise Ways

Entropy-Enthalpy Compensations Fold Proteins in Precise Ways

Applications of a Single Molecule Theory of Protein Dynamics

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