Protein-ligand binding free energy estimation using molecular mechanics and continuum electrostatics. Application to HIV-1 protease inhibitors.

摘要: A method is proposed for the estimation of absolute binding free energy interaction between proteins and ligands. Conformational sampling protein-ligand complex performed by molecular dynamics (MD) in vacuo solvent effect calculated a posteriori solving Poisson or Poisson–Boltzmann equation selected frames trajectory. The written as linear combination buried surface upon complexation, SAS bur, electrostatic ligand protein, Eelec, difference solvation energies isolated ΔGsolv. uses complexation to account non-polar contribution because it less sensitive details structure than van der Waals energy. parameters are developed training set 16 HIV-1 protease-inhibitor complexes known 3D structure. correlation coefficient 0.91 was obtained with an unsigned mean error 0.8 kcal/mol. When applied 25 unknown structures, provides satisfactory experimental pIC 50 without reparametrization.