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Optimizing Multisite λ-Dynamics Throughput with Charge Renormalization
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DOI：10.1021/acs.jcim.2c00047.png)
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Abstract
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With the ability to sample combinations of alchemical perturbations at multiple sites offa small molecule core,multisite lambda-dynamics (MS lambda D) has become an attractive alternative to conventional alchemical free energy methods for exploringlarge combinatorial chemical spaces. However, current software implementations dictate that combinatorial sampling with MS lambda Dmust be performed with a multiple topology model (MTM), which is nontrivial to create by hand, especially for a series of ligandanalogues which may have diverse functional groups attached. This work introduces an automated workflow, referred to asmsld_py_prep, to assist in the creation of a MTM for use with MS lambda D. One approach for partitioning partial atomic charges betweenligands to create a MTM, called charge renormalization, is also presented and rigorously evaluated. Wefind thatmsld_py_prepgreatly accelerates the preparation of MS lambda D ready-to-usefiles and that charge renormalization can provide a successful approach forMTM generation, as long as bookending calculations are applied to correct small differences introduced by charge renormalization.Charge renormalization also facilitates the use of many different forcefield parameters with MS lambda D, broadening the applicability ofMS lambda D for computer-aided drug design.
Keywords:
GENERAL FORCE-FIELD
SOLVATION FREE-ENERGIES
HYDRATION FREE-ENERGIES
DRUG DISCOVERY
SIMULATION
COMPUTATION
AUTOMATION
MECHANICS
SCAFFOLDS
EFFICIENT
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