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Determining the Contribution of the Energy Systems During Exercise
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Estimating Atomic Contributions to Hydration and Binding Using Free Energy Perturbation.
Benedict W J Irwin1, David J Huggins1,2
1Theory of Condensed Matter Group, Cavendish Laboratory , University of Cambridge , 19 J J Thomson Avenue , Cambridge CB3 0HE , United Kingdom.
Journal of Chemical Theory and Computation
|May 2, 2018
Summary
Atom-wise Free Energy Perturbation (AFEP) provides detailed atomic contributions to free energy changes, enhancing molecular dynamics simulations. This method aids in understanding molecular interactions and optimizing drug design by pinpointing key atomic interactions.
Area of Science:
- Computational Chemistry
- Molecular Dynamics
- Biophysics
Background:
- Free Energy Perturbation (FEP) is a valuable method for calculating free energy changes in molecular systems.
- Conventional FEP provides a single value for the overall free energy change.
- There is a need for methods that can dissect free energy contributions at a finer level of detail.
Purpose of the Study:
- To introduce a general method, Atom-wise Free Energy Perturbation (AFEP), that extends FEP simulations.
- To enable the calculation of free energy change contributions from individual atoms.
- To demonstrate the utility of AFEP in analyzing molecular interactions and guiding drug discovery.
Main Methods:
- AFEP is derived from the Zwanzig equation within the exponential averaging method.
- The method partitions the system's total energy into atomic contributions.
- A specific partitioning scheme is applied to group terms corresponding to individual atoms.
Main Results:
- AFEP was applied to calculate hydration free energies for small molecules (methane, methanol, etc.) and caffeine in water.
- The method identified specific atoms with favorable or unfavorable interactions with water.
- AFEP was used to analyze the binding free energy of HIV-1 protease to lopinavir, highlighting atom-specific contributions.
Conclusions:
- AFEP offers a significant advancement over conventional FEP by providing atom-level insights.
- The method can be applied to various system partitions (atoms, groups, amino acids) depending on the research question.
- AFEP has broad applicability in molecular dynamics for physical, chemical, and biochemical studies, particularly in computational drug discovery.
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