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Can One Trust Kinetic and Thermodynamic Observables from Biased Metadynamics Simulations?: Detailed Quantitative Benchmarks on Millimolar Drug Fragment Dissociation

Research output: Contribution to journalArticlepeer-review

Debabrata Pramanik, Zachary Smith, Adam Kells, Pratyush Tiwary

Original languageEnglish
Pages (from-to)3672-3678
Number of pages7
JournalThe journal of physical chemistry. B
Issue number17
Early online date11 Apr 2019
E-pub ahead of print11 Apr 2019
Published2 May 2019

King's Authors


Understanding ligand dissociation mechanisms at an atomic resolution is a highly desired but difficult to achieve objective in experiments as well as in computer simulations. Structural details of the dissociation process are in general hard to capture in experiments, while the relevant time scales are far beyond molecular dynamics (MD) simulations even with the most powerful supercomputers. As such, many different specialized enhanced sampling methods have been proposed that make it possible to efficiently calculate the dissociation mechanisms in protein–ligand systems. However, accurate benchmarks against long unbiased MD simulations are either not reported yet or simply not feasible due to the extremely long time scales. In this manuscript, we consider one such recent method, “infrequent metadynamics”, and benchmark in detail the thermodynamic and kinetic information obtained from this method against extensive unbiased MD simulations for the dissociation dynamics of two different millimolar fragments from the protein FKBP in explicit water with residence times in the nanoseconds to microseconds regime. We find that the metadynamics approach gives the same binding free energy profile, dissociation pathway, and ligand residence time as the unbiased MD, albeit using only 6–50 times lower computational resources. Furthermore, we demonstrate how the metadynamics approach can self-consistently be used to ascertain whether the reweighted kinetic constants are reliable or not. We thus conclude that the answer to the question posed in the title of this manuscript is, statistically speaking, yes.

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