Erratum pubs.acs.org/jcim
Correction to Metadynamics Simulations Distinguish Short- and Long-Residence-Time Inhibitors of Cyclin-Dependent Kinase 8 Donatella Callegari, Alessio Lodola,* Daniele Pala, Silvia Rivara, Marco Mor,* Andrea Rizzi, and Anna Maria Capelli J. Chem. Inf. Model. DOI: 10.1021/acs.jcim.6b00679
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n a recent paper,1 we have described and applied a novel metadynamics protocol able to correctly rank the residence times of protein−ligand complexes of pharmaceutical interest. Our protocol is a modification of the original approach recently proposed by Tiwary and Parrinello.2 After insightful discussions with the authors of the original method, we acknowledge that some sentences in our paper are misleading and they should be rephrased to express our actual opinion. In particular, both in the Introduction and in the Conclusion, we have stated that, regarding the set of CDK8 inhibitors we studied in our work, the approach developed by Tiwary and Parrinello “failed to correctly rank the residence times of this data set”. However, this sentence is not correct because, as reported in the Results and Discussion section, we did not compare our protocol with the original one, but with a modified version of it, where residence times were estimated at simulation times when the acceleration factor α reached its first maximum. These estimates, similar to those previously applied to the analysis of structure-residence times for different series of congeneric ligands,3 actually failed to correctly rank the residence times of this data set. We have to stress, however, that the original method of Tiwary and Parrinello has been applied to a protein−ligand complex simulating full unbinding of the ligand,4 showing that its application provides detailed mechanistic information which is missed by our simplified approach. On the other hand, the metadynamics protocol described in our paper offers a way to get semiquantitative estimations of relative residence times for sets of different ligands, with satisfactory cost and performance for its application in medicinal chemistry projects.
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REFERENCES
(1) Callegari, D.; Lodola, A.; Pala, D.; Rivara, S.; Mor, M.; Rizzi, A.; Capelli, A. M. J. Chem. Inf. Model. 2017, DOI: 10.1021/ acs.jcim.6b00679. (2) Tiwary, P.; Parrinello, M. From Metadynamics to Dynamics. Phys. Rev. Lett. 2013, 111, 230602. (3) Bortolato, A.; Deflorian, F.; Weiss, D. R.; Mason, J. S. Decoding the Role of Water Dynamics in Ligand-Protein Unbinding: CRF1R as a Test Case. J. Chem. Inf. Model. 2015, 55, 1857−1866. (4) Tiwary, P.; Limongelli, V.; Salvalaglio, M.; Parrinello, M. Kinetics of Protein-Ligand Unbinding: Predicting Pathways, Rates, and RateLimiting Steps. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, E386−E391.
Published: February 2, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.jcim.7b00045 J. Chem. Inf. Model. 2017, 57, 386−386
