Accessory mutations balance the marginal stability of the HIV‐1 protease in drug resistance. Issue 3 (21st October 2019)

• Record Type: Journal Article
• Authors: Weikl, Thomas R.; Hemmateenejad, Bahram
• Is Part Of: Proteins. Volume 88:Issue 3(2020)
• Page Start: 476
• Page End: 484
• Publication Date: 2019-10-21
• Subjects: AIDS therapy -- computation -- correlation analysis -- mutation‐induced stability changes -- protein mutations; Proteins -- Periodicals; Proteins -- Periodicals; 572.6
• DOI: 10.1002/prot.25826
• Languages: English
• ISSNs: 0887-3585

Abstract

Abstract: The HIV‐1 protease is a major target of inhibitor drugs in AIDS therapies. The therapies are impaired by mutations of the HIV‐1 protease that can lead to resistance to protease inhibitors. These mutations are classified into major mutations, which usually occur first and clearly reduce the susceptibility to protease inhibitors, and minor, accessory mutations that occur later and individually do not substantially affect the susceptibility to inhibitors. Major mutations are predominantly located in the active site of the HIV‐1 protease and can directly interfere with inhibitor binding. Minor mutations, in contrast, are typically located distal to the active site. A central question is how these distal mutations contribute to resistance development. In this article, we present a systematic computational investigation of stability changes caused by major and minor mutations of the HIV‐1 protease. As most small single‐domain proteins, the HIV‐1 protease is only marginally stable. Mutations that destabilize the folded, active state of the protease therefore can shift the conformational equilibrium towards the unfolded, inactive state. We find that the most frequent major mutations destabilize the HIV‐1 protease, whereas roughly half of the frequent minor mutations are stabilizing. An analysis of protease sequences from patients in treatment indicates that the stabilizing minor mutations are frequently correlated with destabilizing major mutations, and that highly resistant HIV‐1 proteases exhibit significant fractions of stabilizing mutations. Our results thus indicate a central role of minor mutations in balancing the marginal stability of the protease against the destabilization induced by the most frequent major mutations.