Modelling Flexible Protein-Ligand Binding in p38α MAP Kinase using the QUBE Force Field

11 October 2019, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The quantum mechanical bespoke (QUBE) force field is used to retrospectively calculate the relative binding free energy of a series of 17 flexible inhibitors of p38α MAP kinase. The size and flexibility of the chosen molecules represent a stringent test of the derivation of force field parameters from quantum mechanics, and enhanced sampling is required to reduce the dependence of the results on the starting structure. Competitive accuracy with a widely-used biological force field is achieved, indicating that quantum mechanics derived force fields are approaching the accuracy required to provide guidance in prospective drug discovery campaigns.


quantum mechanics
force field
molecular mechanics
free energy

Supplementary materials



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