Journal
MOLECULAR SIMULATION
Volume 42, Issue 13, Pages 1056-1078Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/08927022.2015.1132317
Keywords
QM/MM; free energy; sampling
Funding
- National Science Foundation [CHE-1300209]
- National Institutes of Health [R01GM106443]
- NSF [OCI-1053575, CHE-0840494]
- Grants-in-Aid for Scientific Research [25102008] Funding Source: KAKEN
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM106443] Funding Source: NIH RePORTER
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Due to the higher computational cost relative to pure molecular mechanical (MM) simulations, hybrid quantum mechanical/molecular mechanical (QM/MM) free energy simulations particularly require a careful consideration of balancing computational cost and accuracy. Here, we review several recent developments in free energy methods most relevant to QM/MM simulations and discuss several topics motivated by these developments using simple but informative examples that involve processes in water. For chemical reactions, we highlight the value of invoking enhanced sampling technique (e.g. replica-exchange) in umbrella sampling calculations and the value of including collective environmental variables (e.g. hydration level) in metadynamics simulations; we also illustrate the sensitivity of string calculations, especially free energy along the path, to various parameters in the computation. Alchemical free energy simulations with a specific thermodynamic cycle are used to probe the effect of including the first solvation shell into the QM region when computing solvation free energies. For cases where high-level QM/MM potential functions are needed, we analyse two different approaches: the QM/MM-MFEP method of Yang and co-workers and perturbative correction to low-level QM/MM free energy results. For the examples analysed here, both approaches seem productive although care needs to be exercised when analysing the perturbative corrections.
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