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Computation of Atmospheric Concentrations of Molecular Clusters from ab initio Thermochemistry
Published on: April 8, 2020
Efficient free energy calculations for compounds with multiple stable conformations separated by high energy barriers
Jozef Hritz1, Chris Oostenbrink
1Leiden Amsterdam Center for Drug Research, Division of Molecular Toxicology, VU University Amsterdam, The Netherlands.
The Journal of Physical Chemistry. B
|September 3, 2009
Summary
Calculating free energy for complex molecules is now efficient with the enhanced sampling-one step perturbation (ES-OS) method. This approach requires only one simulation to accurately determine conformational distributions and free energy differences for similar compounds.
Area of Science:
- Computational Chemistry
- Molecular Dynamics
- Biophysical Chemistry
Background:
- Calculating free energy for compounds with high intramolecular energy barriers is computationally demanding due to insufficient conformational sampling.
- Existing methods are often too slow for practical applications involving such challenging molecular targets.
Purpose of the Study:
- To introduce an efficient enhanced sampling-one step perturbation (ES-OS) method for free energy calculations.
- To enable accurate determination of conformational distributions and free energy differences using a single simulation.
Main Methods:
- Development and application of the enhanced sampling-one step perturbation (ES-OS) method.
- Utilizing soft-core interactions in a single molecular dynamics simulation of a reference state.
- Validation against Hamiltonian replica exchange simulations and experimental data (3J(C4,H1') coupling constant).
Main Results:
- The ES-OS method efficiently calculates free energy differences for chemically similar compounds, including 8-substituted GTP analogs with high energy barriers.
- Results were validated against established methods and experimental data, demonstrating high reliability.
- Solvation free energies, lipophilicities (log P), and contributions from different conformational regions were calculated.
Conclusions:
- The ES-OS method provides a computationally efficient and reliable approach for free energy calculations of complex molecules.
- Derived multiconformational free energy formulas offer general applicability for diverse compounds.
- This method significantly advances the practical application of free energy calculations in chemistry and biology.
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