TY - JOUR
T1 - CHARMM-GUI EnzyDocker for Protein-Ligand Docking of Multiple Reactive States along a Reaction Coordinate in Enzymes
AU - Suh, Donghyuk
AU - Schwartz, Renana
AU - Gupta, Prashant Kumar
AU - Zev, Shani
AU - Major, Dan T.
AU - Im, Wonpil
N1 - Publisher Copyright:
© 2025 The Authors. Published by American Chemical Society.
PY - 2025/2/25
Y1 - 2025/2/25
N2 - Enzymes play crucial roles in all biological systems by catalyzing a myriad of chemical reactions. These reactions range from simple one-step processes to intricate multistep cascades. Predicting mechanistically appropriate binding modes along a reaction pathway for substrate, product, and all reaction intermediates and transition states is a daunting task. To address this challenge, special docking programs like EnzyDock have been developed. Yet, running such docking simulations is complicated due to the nature of multistep enzyme processes. This work presents CHARMM-GUI EnzyDocker, a web-based cyberinfrastructure designed to streamline the preparation and running of EnzyDock docking simulations. The development of EnzyDocker has been achieved through integration of existing CHARMM-GUI modules, such as PDB Reader and Manipulator, Ligand Designer, and QM/MM Interfacer. In addition, new functionalities have been developed to facilitate a one-stop preparation of multistate and multiscale docking systems and enable interactive and intuitive ligand modifications and flexible protein residues selections. A simple setup related to multiligand docking is automatized through intuitive user interfaces. EnzyDocker offers support for standard classical docking and QM/MM docking with CHARMM built-in semiempirical engines. Automated consensus restraints for incorporating experimental knowledge into the docking are facilitated via a maximum common substructure algorithm. To illustrate the robustness of EnzyDocker, we conducted docking simulations of three enzyme systems: dihydrofolate reductase, SARS-CoV-2 Mpro, and the diterpene synthase CotB2. In addition, we have created four tutorial videos about these systems, which can be found at https://www.charmm-gui.org/demo/enzydock. EnzyDocker is expected to be a valuable and accessible web-based tool that simplifies and accelerates the setup process for multistate docking for enzymes.
AB - Enzymes play crucial roles in all biological systems by catalyzing a myriad of chemical reactions. These reactions range from simple one-step processes to intricate multistep cascades. Predicting mechanistically appropriate binding modes along a reaction pathway for substrate, product, and all reaction intermediates and transition states is a daunting task. To address this challenge, special docking programs like EnzyDock have been developed. Yet, running such docking simulations is complicated due to the nature of multistep enzyme processes. This work presents CHARMM-GUI EnzyDocker, a web-based cyberinfrastructure designed to streamline the preparation and running of EnzyDock docking simulations. The development of EnzyDocker has been achieved through integration of existing CHARMM-GUI modules, such as PDB Reader and Manipulator, Ligand Designer, and QM/MM Interfacer. In addition, new functionalities have been developed to facilitate a one-stop preparation of multistate and multiscale docking systems and enable interactive and intuitive ligand modifications and flexible protein residues selections. A simple setup related to multiligand docking is automatized through intuitive user interfaces. EnzyDocker offers support for standard classical docking and QM/MM docking with CHARMM built-in semiempirical engines. Automated consensus restraints for incorporating experimental knowledge into the docking are facilitated via a maximum common substructure algorithm. To illustrate the robustness of EnzyDocker, we conducted docking simulations of three enzyme systems: dihydrofolate reductase, SARS-CoV-2 Mpro, and the diterpene synthase CotB2. In addition, we have created four tutorial videos about these systems, which can be found at https://www.charmm-gui.org/demo/enzydock. EnzyDocker is expected to be a valuable and accessible web-based tool that simplifies and accelerates the setup process for multistate docking for enzymes.
UR - http://www.scopus.com/inward/record.url?scp=85217745685&partnerID=8YFLogxK
U2 - 10.1021/acs.jctc.4c01691
DO - 10.1021/acs.jctc.4c01691
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C2 - 39950957
AN - SCOPUS:85217745685
SN - 1549-9618
VL - 21
SP - 2118
EP - 2128
JO - Journal of Chemical Theory and Computation
JF - Journal of Chemical Theory and Computation
IS - 4
ER -