Prediction of HIV drug resistance based on the 3D protein structure: Proposal of molecular field mapping

PLoS One. 2021 Aug 4;16(8):e0255693. doi: 10.1371/journal.pone.0255693. eCollection 2021.

Abstract

A method for predicting HIV drug resistance by using genotypes would greatly assist in selecting appropriate combinations of antiviral drugs. Models reported previously have had two major problems: lack of information on the 3D protein structure and processing of incomplete sequencing data in the modeling procedure. We propose obtaining the 3D structural information of viral proteins by using homology modeling and molecular field mapping, instead of just their primary amino acid sequences. The molecular field potential parameters reflect the physicochemical characteristics associated with the 3D structure of the proteins. We also introduce the Bayesian conditional mutual information theory to estimate the probabilities of occurrence of all possible protein candidates from an incomplete sequencing sample. This approach allows for the effective use of uncertain information for the modeling process. We applied these data analysis techniques to the HIV-1 protease inhibitor dataset and developed drug resistance prediction models with reasonable performance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / metabolism*
  • Bayes Theorem
  • Data Analysis
  • Drug Resistance, Viral / genetics*
  • Genotype
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV Protease / chemistry*
  • HIV Protease / genetics
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemistry*
  • HIV Protease Inhibitors / metabolism*
  • HIV-1 / enzymology*
  • Humans
  • Machine Learning
  • Models, Chemical
  • Models, Molecular
  • Protein Conformation
  • Sequence Analysis, Protein / methods

Substances

  • Anti-HIV Agents
  • HIV Protease Inhibitors
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1

Grants and funding

This work was financially supported in part by the Japan Society for the Promotion of Science in the form of grants award to RO (KAKENHI Grant Number JP20J15557) and MT (KAKENHI Grant Number JP18K06747). Computations were partially performed on the NIG supercomputer at ROIS National Institute of Genetics.