scholarly journals Efficient Determination of Protein–Protein Standard Binding Free Energies from First Principles

2013 ◽  
Vol 9 (8) ◽  
pp. 3789-3798 ◽  
Author(s):  
James C. Gumbart ◽  
Benoît Roux ◽  
Christophe Chipot
Keyword(s):  
First Principles ◽  
Free Energies ◽  
Binding Free Energies

scholarly journals Accurate absolute free energies for ligand–protein binding based on non-equilibrium approaches

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Vytautas Gapsys ◽  
Ahmet Yildirim ◽  
Matteo Aldeghi ◽  
Yuriy Khalak ◽  
David van der Spoel ◽  
...  
Keyword(s):  
Free Energy ◽  
First Principles ◽  
Binding Free Energy ◽  
Free Energy Perturbation ◽  
Free Energies ◽  
Hamiltonian Replica Exchange ◽  
Current State ◽  
Energy Perturbation ◽  
Binding Free Energies ◽  
Non Equilibrium

AbstractThe accurate calculation of the binding free energy for arbitrary ligand–protein pairs is a considerable challenge in computer-aided drug discovery. Recently, it has been demonstrated that current state-of-the-art molecular dynamics (MD) based methods are capable of making highly accurate predictions. Conventional MD-based approaches rely on the first principles of statistical mechanics and assume equilibrium sampling of the phase space. In the current work we demonstrate that accurate absolute binding free energies (ABFE) can also be obtained via theoretically rigorous non-equilibrium approaches. Our investigation of ligands binding to bromodomains and T4 lysozyme reveals that both equilibrium and non-equilibrium approaches converge to the same results. The non-equilibrium approach achieves the same level of accuracy and convergence as an equilibrium free energy perturbation (FEP) method enhanced by Hamiltonian replica exchange. We also compare uni- and bi-directional non-equilibrium approaches and demonstrate that considering the work distributions from both forward and reverse directions provides substantial accuracy gains. In summary, non-equilibrium ABFE calculations are shown to yield reliable and well-converged estimates of protein–ligand binding affinity.

New Coarse Variables for the Accurate Determination of Standard Binding Free Energies

2017 ◽  
Vol 13 (11) ◽  
pp. 5173-5178 ◽  
Author(s):  
Haohao Fu ◽  
Wensheng Cai ◽  
Jérôme Hénin ◽  
Benoît Roux ◽  
Christophe Chipot
Keyword(s):  
Accurate Determination ◽  
Free Energies ◽  
Binding Free Energies

The spectrophotometric solvent sorting method for the determination of free energies of transfer of individual ions—a critical appraisal

1983 ◽  
Vol 36 (9) ◽  
pp. 1739 ◽  
Author(s):  
CF Wells
Keyword(s):  
First Principles ◽  
Structural Changes ◽  
Critical Appraisal ◽  
Solvent Mixtures ◽  
Free Energies ◽  
Dominant Effect ◽  
Free Energy Of Transfer ◽  
Solvent Molecules ◽  
Energy Of Transfer

The spectrophotometric method for determining values for the free energy of transfer of the proton from water into water + co-solvent mixtures at mole fractions of co-solvent up to x2 ≈ 0.3 is examined critically from first principles. It is found that some corrections become significant at the higher x2 in this range and these are applied to all the co-solvents used. The new values for ΔGt�(H+) are then used to calculate new values for ΔGt� (X-) from ΔGt�(HX) and new values for ΔGt�(M+) and (M2+)from ΔGt�(MX) and ΔGT�(MX2). New electrochemical, solubility and pK data are incorporated into these calculations, resulting in ΔGt� values for some additional ions for several co-solvents. The ΔGt� values for all co-solvents are compared and contrasted, and it is concluded that structural changes in the solvent have a dominant effect in determining these values. The evidence for molecular rearrangements involving solvent molecules in the neighbourhood of the ions resulting from the transfer is examined.

Determination of the relative binding free energies of peptide inhibitors to the HIV-1 protease

1991 ◽  
Vol 34 (8) ◽  
pp. 2654-2659 ◽  
Author(s):  
David M. Ferguson ◽  
Randall J. Radmer ◽  
Peter A. Kollman
Keyword(s):  
Peptide Inhibitors ◽  
Free Energies ◽  
Relative Binding ◽  
Hiv 1 ◽  
Binding Free Energies

Chemical equilibrium and chemical kinetics

2018 ◽  
Author(s):  
Dennis Sherwood ◽  
Paul Dalby
Keyword(s):  
Free Energy ◽  
Equilibrium Constant ◽  
Gibbs Free Energy ◽  
Chemical Kinetics ◽  
Chemical Equilibrium ◽  
First Principles ◽  
Effect Of Temperature ◽  
Total System ◽  
Free Energies

Building on the previous chapter, this chapter examines gas phase chemical equilibrium, and the equilibrium constant. This chapter takes a rigorous, yet very clear, ‘first principles’ approach, expressing the total Gibbs free energy of a reaction mixture at any time as the sum of the instantaneous Gibbs free energies of each component, as expressed in terms of the extent-of-reaction. The equilibrium reaction mixture is then defined as the point at which the total system Gibbs free energy is a minimum, from which concepts such as the equilibrium constant emerge. The chapter also explores the temperature dependence of equilibrium, this being one example of Le Chatelier’s principle. Finally, the chapter links thermodynamics to chemical kinetics by showing how the equilibrium constant is the ratio of the forward and backward rate constants. We also introduce the Arrhenius equation, closing with a discussion of the overall effect of temperature on chemical equilibrium.

scholarly journals Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Germano Heinzelmann ◽  
Michael K. Gilson
Keyword(s):  
Free Energy ◽  
Early Stage ◽  
Binding Free Energy ◽  
Low Cost ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Energy Calculations ◽  
Drug Candidates ◽  
Binding Free Energy Calculations ◽  
Binding Free Energies

AbstractAbsolute binding free energy calculations with explicit solvent molecular simulations can provide estimates of protein-ligand affinities, and thus reduce the time and costs needed to find new drug candidates. However, these calculations can be complex to implement and perform. Here, we introduce the software BAT.py, a Python tool that invokes the AMBER simulation package to automate the calculation of binding free energies for a protein with a series of ligands. The software supports the attach-pull-release (APR) and double decoupling (DD) binding free energy methods, as well as the simultaneous decoupling-recoupling (SDR) method, a variant of double decoupling that avoids numerical artifacts associated with charged ligands. We report encouraging initial test applications of this software both to re-rank docked poses and to estimate overall binding free energies. We also show that it is practical to carry out these calculations cheaply by using graphical processing units in common machines that can be built for this purpose. The combination of automation and low cost positions this procedure to be applied in a relatively high-throughput mode and thus stands to enable new applications in early-stage drug discovery.

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