Chemical neighborhood exploration for substrate discovery in biocatalysis
Abstract
Predicting the substrate reactivity strength for a given biocatalyst remains a central challenge in computational biocatalysis. Here, we present Subdate, a modular workflow that combines descriptor-guided organization of substrate analogs with ab initio metadynamics simulations to prioritize reactive candidates. The workflow integrates i) substrate library construction, ii) conformer generation and descriptors set definition, iii) library clustering, iv) representative-substrate selection, and v) reaction-barrier quantitative prediction. Applied to selected biocatalysts (human butyrylcholinesterase and the catalytic antibody A17) sharing an SN2 reaction mechanism, Subdate quantitatively identifies reactivity trends that match experimental kinetic measurements. The developed workflow provides a mechanism-aware strategy for reactive substrate prioritization for efficient sampling through the chemical library in biocatalysis.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (11)
Yaroslav V. Solovev
Department of Peptide and Protein Technologies, M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
Nikita N. Kostin
Department of Peptide and Protein Technologies, M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
Yuri A. Prokopenko
Department of Peptide and Protein Technologies, M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
Patrick Masson
Ivan V. Smirnov
Department of Peptide and Protein Technologies, M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
Hongkai Zhang
Frontiers Science Center for New Organic Matter, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Academy for Advanced Interdisciplinary Studies
Wei Zheng
Igor A. Yaroshevich
Department of Biophysics, Faculty of Biology, Lomonosov Moscow State University
Alexey V. Stepanov
Department of Integrative Structural and Computational Biology, The Scripps Research Institute
Petr A. Popov
School of Science, Constructor University Bremen
Alexander G. Gabibov
Department of Peptide and Protein Technologies, M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences