Abstract
Accurate prediction of binding free energies is critical to streamlining the drug development and protein design process. With the advent of GPU acceleration, absolute alchemical methods, which simulate the removal of ligand electrostatics and van der Waals interactions with the protein, have become routinely accessible and provide a physically rigorous approach that enables full consideration of flexibility and solvent interaction. However, standard explicit solvent simulations are unable to model protonation or electronic polarization changes upon ligand transfer from water to the protein interior, leading to inaccurate prediction of binding affinities for charged molecules. Here, we perform extensive simulation totaling ∼540 μs to benchmark the impact of modeling conditions on predictive accuracy for absolute alchemical simulations. Binding to urokinase plasminogen activator (UPA), a protein frequently overexpressed in metastatic tumors, is evaluated for a set of 10 inhibitors with extended flexibility, highly charged character, and titratable properties. We demonstrate that the alchemical simulations can be adapted to utilize the MBAR/PBSA method to improve the accuracy upon incorporating electronic polarization, highlighting the importance of polarization in alchemical simulations of binding affinities. Comparison of binding energy prediction at various protonation states indicates that proper electrostatic setup is also crucial in binding affinity prediction of charged systems, prompting us to propose an alternative binding mode with protonated ligand phenol and Hid-46 at the binding site, a testable hypothesis for future experimental validation.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.