QresFEP

QresFEP predicts the effects of single-point amino acid mutations on protein stability and protein–ligand binding using free energy calculations.

Key Features:

• Comprehensive Coverage: Extends free energy protocols to cover all possible amino acid mutations and employs the latest OPLS-AA force field.
• MD Integration: Implemented with the molecular dynamics software Q.
• Sampling and Estimators: Employs optimized sampling parameters and uses Zwanzig's exponential formula and the Bennett acceptance ratio for free energy estimation.
• Hydration Free Energies: Benchmarked for estimation of hydration free energies of amino acid side-chain mimics, including charged analogues.
• Protein–Ligand Benchmark: Accurately predicted effects of 16 mutations on antagonist BIBP3226 binding to the neuropeptide Y1 G protein-coupled receptor, consistent with experimental data.
• Thermal Stability Benchmark: Characterized 43 T4-lysozyme mutations to assess thermal stability, achieving performance comparable to alternative FEP approaches.

Scientific Applications:

• Protein Stability Assessment: Quantitative prediction of mutation-induced changes in protein thermal stability.
• Binding Affinity Prediction: Prediction of mutation effects on ligand binding affinity, including GPCR antagonist binding.
• Drug Design and Development: Informing structure-based drug design by predicting mutational impacts on therapeutic targets.
• Biophysical Studies: Investigating mutation effects on protein dynamics and hydration thermodynamics of side-chain analogues.

Methodology:

Performs free energy perturbation (FEP) calculations using the OPLS-AA force field with optimized sampling parameters, applying Zwanzig's exponential formula and the Bennett acceptance ratio, and is implemented with the molecular dynamics software Q.