Publication: MovableType Software for Fast Free-Energy based Virtual Screening: Protocol Development, Deployment, Validation and Assessment

Abstract: For decades, the complicated energy surfaces found in macromolecular, protein:ligand structures, which require large amounts of computational time and resources for energy state sampling, have been an inherent obstacle to fast, routine free energy estimation in industrial drug discovery efforts. Beginning in 2013, the Merz research group addressed this cost with the introduction of a novel sampling methodology termed “Movable Type” (MT). Using numerical integration methods, the MT method reduces the computational expense for energy state sampling by independently calculating each atomic partition function from an initial molecular conformation in order to estimate the molecular free energy using ensembles of the atomic parti-tion functions. In this work, we report a software package (the DivCon Discovery Suite with the MovableType module from QuantumBio Inc.) which performs this MT free energy estimation protocol in a fast, fully encapsulated manner. We discuss the computational procedures and improvements to the original work, and we detail the corresponding settings for this software package. Finally, we introduce two validation benchmarks to evaluate the overall robustness of the method against a broad range of protein:ligand structural cases. With these publicly available benchmarks, we show that the method is able to use a variety of input types and parameters, and to exhibit comparable predictability whether the method is presented with “expensive” X-ray structures or “inexpensively docked” theoretical models. We also explore some next steps for the method. Note: The Movable-Type software is available at http://www.quantumbioinc.com/

Authors: Zheng Zheng, Oleg Borbulevych, Hao Liu, Jianpeng Deng, Roger I Martin, and Lance Westerhoff

Reference: J. Chem. Inf. Model. 2020