HARP

HARP predicts the structural and functional consequences of systematic missense mutations in drug targets of Mycobacterium leprae to assess antimicrobial resistance.

Key Features:

• Computational Saturation Mutagenesis: Systematically mutates each amino acid residue to predict changes in thermodynamic stability and affinity of protein subunits, ligands, and nucleic acids.
• Target Proteins: Analyzes three drug targets in M. leprae: Dihydropteroate Synthase (DHPS) for dapsone, RNA Polymerase (RNAP) for rifampin, and DNA Gyrase (GYR) for ofloxacin.
• Structure Modeling: Builds protein models using template-based comparative modeling when experimental structures are absent from the Protein Data Bank.
• Mutation Analysis: Generates and evaluates 80,902 systematic missense mutations across the three target proteins using a suite of in-house developed and published prediction software.
• Consensus Impact Estimation: Assigns qualitative impact scores by integrating physicochemical property assessments and categorical grouping of stability and affinity predictions.

Scientific Applications:

• Resistance profiling: Predicts mutation-driven antimicrobial resistance phenotypes in Mycobacterium leprae.
• Mechanistic interpretation: Assesses how specific missense mutations alter protein stability and interactions that affect drug efficacy.
• Therapeutic guidance: Informs identification of potential resistance profiles and guides development of new therapeutic strategies against leprosy.

Methodology:

Applies computational saturation mutagenesis to generate 80,902 missense mutations across DHPS, RNAP, and GYR; constructs protein models by template-based comparative modeling when PDB structures are unavailable; evaluates impacts on thermodynamic stability and affinities to subunits, ligands, and nucleic acids using in-house and published prediction software; and derives consensus qualitative impact scores from physicochemical properties and categorical grouping of stability and affinity predictions.