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Angew Chem Int Ed Engl DOI:10.1002/anie.202200983

Protein Flexibility and Dissociation Pathway Differentiation Can Explain Onset Of Resistance Mutations in Kinases.

Publication TypeJournal Article
Year of Publication2022
AuthorsShekhar, M, Smith, Z, Seeliger, M, Tiwary, P
JournalAngew Chem Int Ed Engl
Date Published2022 Apr 29

Understanding how mutations render a drug ineffective is a problem of immense relevance. Often the mechanism through which mutations cause drug resistance can be explained purely through thermodynamics. However, the more perplexing situation is when two proteins have the same drug binding affinities but different residence times. In this work, we demonstrate how all-atom molecular dynamics simulations using recent developments grounded in statistical mechanics can provide a detailed mechanistic rationale for such variances. We discover dissociation mechanisms for the anti-cancer drug Imatinib (Gleevec) against wild-type and the N368S mutant of Abl kinase. We show how this point mutation triggers far-reaching changes in protein's flexibility and leads to a different, much faster, drug dissociation pathway. We believe that this work marks an efficient and scalable approach to obtain mechanistic insight into resistance mutations in biomolecular receptors that are hard to explain using a structural perspective.


Alternate JournalAngew Chem Int Ed Engl
PubMed ID35486370