Simple, Intuitive Calculations of Free Energy of Binding for Protein−Ligand Complexes. 3. The Free Energy Contribution of Structural Water Molecules in HIV-1 Protease Complexes

A free-energy-based approach is used to describe the mechanism through which chaperonin-containing TCP-1 (CCT) folds the filament-forming cytoskeletal protein actin, which is one of its primary substrates. The experimental observations on the actin folding and unfolding pathways are collated and then re-examined from this perspective, allowing us to determine the position of the CCT intervention on the actin free-energy folding landscape. The essential role for CCT in actin folding is to provide a free-energy contribution from its ATP cycle, which drives actin to fold from a stable, trapped intermediate I 3 , to a less stable but now productive folding intermediate I 2 . We develop two hypothetical mechanisms for actin folding founded upon concepts established for the bacterial type I chaperonin GroEL and extend them to the much more complex CCT system of eukaryotes. A new model is presented in which CCT facilitates free-energy transfer through direct coupling of the nucleotide hydrolysis cycle to the phases of actin substrate maturation.

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Intriguing Role of Water in Plant Hormone Perception

10.1101/2021.10.04.462894 ◽

2021 ◽

Author(s):

Chuankai Zhao ◽

Diego Eduardo Kleiman ◽

Diwakar Shukla

Keyword(s):

Free Energy ◽

Plant Growth ◽

Binding Site ◽

Plant Hormones ◽

Plant Hormone ◽

Water Molecules ◽

Water Displacement ◽

Dynamics Simulations ◽

Free Energy Of Binding

Plant hormones are small molecules that regulate plant growth, development, and responses to biotic and abiotic stresses. Plant hormones are specifically recognized by the binding site of their receptors. In this work, we investigated the role of water displacement and reorganization at the binding site of plant receptors on the binding of eight classes of phytohormones (auxin, jasmonate, gibberellin, strigolactone, brassinosteroid, cytokinin, salicylic acid, and abscisic acid) using extensive molecular dynamics simulations and inhomogeneous solvation theory. Our findings demonstrated that displacement of water molecules by phytohormones contributes to free energy of binding via entropy gain and is associated with free energy barriers. Also, our results have shown that displacement of unfavorable water molecules in the binding site can be exploited in rational agrochemical design. Overall, this study uncov- ers the role of water molecules in plant hormone perception, which creates new avenues for agrochemical design to target plant growth and development.

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The Free Energy Contribution of SH3 and SH2 in c-Abl 1b Autoinhibition Mechanism via a Computational Structure-Based Model

Biophysical Journal ◽

10.1016/j.bpj.2013.11.1491 ◽

2014 ◽

Vol 106 (2) ◽

pp. 253a-254a

Author(s):

Ilaria Mereu ◽

Ludovico Sutto ◽

Francesco L. Gervasio

Keyword(s):

Free Energy ◽

Energy Contribution ◽

Computational Structure ◽

Free Energy Contribution

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Computational approach for molecular design using free energy contribution analysis

10.1063/1.5079058 ◽

2018 ◽

Author(s):

Toshio Asada ◽

Pradipta Bandyopadhyay ◽

Shiro Koseki

Keyword(s):

Free Energy ◽

Molecular Design ◽

Computational Approach ◽

Energy Contribution ◽

Contribution Analysis ◽

Free Energy Contribution

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QUANTUM CALCULATION OF PROTEIN SOLVATION AND PROTEIN–LIGAND BINDING FREE ENERGY FOR HIV-1 PROTEASE/WATER COMPLEX

Journal of Theoretical and Computational Chemistry ◽

10.1142/s0219633609005313 ◽

2009 ◽

Vol 08 (06) ◽

pp. 1265-1279 ◽

Cited By ~ 21

Author(s):

YAN TONG ◽

YE MEI ◽

JOHN Z. H. ZHANG ◽

LI L. DUAN ◽

QING-GANG ZHANG

Keyword(s):

Free Energy ◽

Binding Free Energy ◽

Minimum Energy ◽

Polarizable Continuum Model ◽

Ionization State ◽

Quantum Mechanical Method ◽

Almost All ◽

Free Energy Contribution ◽

Hiv 1

HIV-1 protease (PR) is a primary target for anti-HIV therapeutics. A well conserved water molecule, denoted as W301, is found in almost all the crystallographic structures of PR/inhibitor complexes and it plays an important role in PR/inhibitor binding. As the PR/inhibitor interaction depends on the ionization state of the cleavage site which contains an aspartyl dyad (Asp25/Asp25′), the determination of the protonation states of aspartyl dyad in PR may be essential for drug design. In this study, a linear scaling quantum mechanical method, molecular fragmentation with conjugate caps (MFCC), is used for interaction study of PR/ABT-538 and W301 at four different monoprotonation states of the Asp25/Asp25′. Combined method of MFCC and conductor-like polarizable continuum model (CPCM) is applied in binding affinity calculation for four minimum energy structures which are extracted from four different molecular dynamics trajectories corresponding to four different monoprotonation states of Asp25/Asp25′. Our result is in good agreement with previous result obtained by FEP/TI method, showing that the conserved W301 contributes significantly to the binding free energy of PR/ABT-538 complex and different protonation states of Asp25/Asp25′ have significant impact on the binding free energy contribution from W301.

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