#6 · Structural bio & protein design

Free energy and coarse-grained physics methods for biomolecular binding and interfaces

The common thread is the use of explicit physical energy functions or molecular dynamics sampling to evaluate binding and structural properties. Four relative binding free energy engines are benchmarked head-to-head on shared Amber force fields, while absolute binding FEP is used to classify integrin ligands by the conformation they stabilize, and FEP with coupling and conformational corrections predicts Fc-FcRn binding energy changes for antibody variants. Coarse-grained energetics enter the workflow in two places: MARTINI2 is implemented in HADDOCK3 for faster protein-protein sampling and scoring, and Martini Mapper automates Martini 3 models from SMILES across 1075 molecules. MD-derived analyses appear in PP-MAPS, which aggregates pharmacophore interactions from protein-peptide trajectories, and AlphaUnfold, which applies short high-pressure NAMD3 runs to AlphaFold3 models to flag fragile regions. FMOPhore pairs fragment molecular orbital calculations with pharmacophore models to classify hotspot residues. Novelty lies mainly in head-to-head benchmarking and in carrying coarse-grained and MD-derived energetics into docking and interface analysis.