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Conserved Binding Sites01:49

Conserved Binding Sites

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Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
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The free energy change for a reaction that occurs under the standard conditions of 1 bar pressure and at 298 K is called the standard free energy change. Since free energy is a state function, its value depends only on the conditions of the initial and final states of the system. A convenient and common approach to the calculation of free energy changes for physical and chemical reactions is by use of widely available compilations of standard state thermodynamic data. One method involves the...
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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
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One of the challenges of using the second law of thermodynamics to determine if a process is spontaneous is that it requires measurements of the entropy change for the system and the entropy change for the surroundings. An alternative approach involving a new thermodynamic property defined in terms of system properties only was introduced in the late nineteenth century by American mathematician Josiah Willard Gibbs. This new property is called the Gibbs free energy (G) (or simply the free...
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Computational Tools for Accurate Binding Free-Energy Prediction.

Maria M Reif1, Martin Zacharias2

  • 1Physics Department (T38), Technische Universität München, Garching, Germany.

Methods in Molecular Biology (Clifton, N.J.)
|December 10, 2021
PubMed
Summary

Computational methods now accurately predict binding affinity, or absolute binding free energy, crucial for understanding biomolecular interactions. This guide details thermodynamic principles and simulation techniques for molecular life sciences.

Keywords:
Binding free energyDouble decouplingFree-energy calculationMolecular dynamics simulationsPotential of mean force

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Area of Science:

  • Thermodynamics
  • Computational Chemistry
  • Molecular Biology

Background:

  • Quantitative thermodynamic understanding of noncovalent (bio)molecular association is vital in molecular life sciences.
  • Binding affinity, or absolute binding free energy, is a key metric for characterizing biomolecular association.
  • Computational prediction of binding free energies has significantly advanced in accuracy, speed, and usability.

Purpose of the Study:

  • To provide an overview of the definition and computational determination of absolute free energies.
  • To outline the theoretical basis of potential of mean force and double decoupling calculations.
  • To offer practical guidance on setting up molecular simulations for binding free energy calculations.

Main Methods:

  • Overview of computational approaches for defining and determining absolute free energies.
  • Detailed explanation of the theoretical underpinnings of potential of mean force (PMF) and double decoupling (DD) methods.
  • Strategies for mitigating sampling challenges using restraints in molecular simulations.

Main Results:

  • The chapter provides a theoretical framework for calculating absolute binding free energies.
  • It details two reliable computational methods: PMF and DD calculations.
  • It addresses the sampling problem and offers solutions using restraints.

Conclusions:

  • Advanced computational methods enable accurate prediction of biomolecular binding affinities.
  • Understanding the thermodynamics of molecular interactions is enhanced through these computational tools.
  • Practical instructions are provided for implementing these simulations using common molecular dynamics engines.