Structure-Based Analysis of Protein Binding Pockets Using Von Neumann Entropy

Forouzesh, Negin; Kazemi, Mohammad Reza; Mohades, Ali

doi:10.1007/978-3-319-08171-7_27

Cited by 4 publications

(2 citation statements)

References 17 publications

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“…The discussed entropy idea cuts across multiple disciplines. For instance, von Neumann entropy was used as a measure of the complexity of protein binding pockets, networks, and graphs . Here, our focus is on the robustness of optimal solutions with an application to a problem related to computational drug discovery.…”

Section: Materials and Methodsmentioning

confidence: 99%

Multidimensional Global Optimization and Robustness Analysis in the Context of Protein–Ligand Binding

Forouzesh

Mukhopadhyay

Watson

et al. 2020

J. Chem. Theory Comput.

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Accuracy of protein–ligand binding free energy calculations utilizing implicit solvent models is critically affected by parameters of the underlying dielectric boundary, specifically, the atomic and water probe radii. Here, a global multidimensional optimization pipeline is developed to find optimal atomic radii specifically for protein–ligand binding calculations in implicit solvent. The computational pipeline has these three key components: (1) a massively parallel implementation of a deterministic global optimization algorithm (VTDIRECT95), (2) an accurate yet reasonably fast generalized Born implicit solvent model (GBNSR6), and (3) a novel robustness metric that helps distinguish between nearly degenerate local minima via a postprocessing step of the optimization. A graph-based “kT-connectivity” approach to explore and visualize the multidimensional energy landscape is proposed: local minima that can be reached from the global minimum without exceeding a given energy threshold (kT) are considered to be connected. As an illustration of the capabilities of the optimization pipeline, we apply it to find a global optimum in the space of just five radii: four atomic (O, H, N, and C) radii and water probe radius. The optimized radii, ρW = 1.37 Å, ρC = 1.40 Å, ρH = 1.55 Å, ρN = 2.35 Å, and ρO = 1.28 Å, lead to a closer agreement of electrostatic binding free energies with the explicit solvent reference than two commonly used sets of radii previously optimized for small molecules. At the same time, the ability of the optimizer to find the global optimum reveals fundamental limits of the common two-dielectric implicit solvation model: the computed electrostatic binding free energies are still almost 4 kcal/mol away from the explicit solvent reference. The proposed computational approach opens the possibility to further improve the accuracy of practical computational protocols for binding free energy calculations.

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Section: Materials and Methodsmentioning

confidence: 99%

Multidimensional Global Optimization and Robustness Analysis in the Context of Protein–Ligand Binding

Forouzesh

Mukhopadhyay

Watson

et al. 2020

J. Chem. Theory Comput.

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“…Entropy is a very broad concept of disorder, having definitions and applications in thermodynamics, modelling the behaviour of the energy of physical systems [1,10,11], information theory as a model of system complexity [12] and economics, to describe the diffusion of money into a system which it may not be freely extracted from [13].…”

Section: Definitionsmentioning

confidence: 99%

UQ eSpace

Kratzer¹

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This thesis details the behaviour of the entropy of ideal gases when gravitation is considered and significant. This analysis is applied to the behaviour of the Carnot cycle. This thesis then discusses how this interaction of gravity and entropy affects the behaviour of this cycles when considering conventional engineering thermodynamics and Newtonian gravity. The operation of cycles with a working fluid with negative effective specific heat is discussed. An estimate of the entropy of the gravitational field is made for Newtonian gravity considerations, and this is compared to other gravitational field entropy estimates. The derived estimate of the gravitational field at the gravitational limit is found to be: S GF = 2mR ln RT r Gm (1) An improvement to the Virial theorem is proposed, where the kinetic and gravitational potential energies of a gravitationally dominated system are expected to approach the relation E k = − 3 4 E g. An update to the Jean's length of a collapsing gas cloud is derived from this expression. The reversal of Carnot cycle operation due to gravitational effects is discussed, along with some possible effects this may have on space engineering design. We find that in a gravitationally dominated system, the net work from a Carnot cycle reverses in direction and reduces to 1/3 of its non-gravitational magnitude while the efficiency is unaffected. i The Author would like to offer their sincere thanks to the people who made the completion of this thesis possible. To my Mother and Father, I cannot fully express my gratitude. Without your hard work and sacrifice this work could never have been possible. Without you I would not be the person I am today. To my old teacher Roger Boyd I give my thanks for inspiring me to enter the world of engineering, science and mathematical study. To my good friends Cian Langan, Adam Clark, Brendan Gallpen, Connor Jackson and Trent Newton I give my thanks for all of the good times that have helped me through this degree. You have all been my muses. I would like to thank Amanda Lee for putting up with me during the stressful times I've had while working on this thesis, and always being there comfort me in times of need. And finally, I would like to thank my advisor Alexander Klimenko for guiding me through this work and for believing in my ability, even when I didn't. Thank you all.

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Protein-Ligand Binding with Applications in Molecular Docking

Mishra

Forouzesh

2012

Algorithms and Methods in Structural Bioinformatics

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Structure-Based Analysis of Protein Binding Pockets Using Von Neumann Entropy

Cited by 4 publications

References 17 publications

Multidimensional Global Optimization and Robustness Analysis in the Context of Protein–Ligand Binding

Multidimensional Global Optimization and Robustness Analysis in the Context of Protein–Ligand Binding

UQ eSpace

Protein-Ligand Binding with Applications in Molecular Docking

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