Ligand Binding Affinities from MD Simulations

• Published in: Accounts of chemical research Vol. 35; no. 6; pp. 358 - 365
• Main Authors: Åqvist, Johan, Luzhkov, Victor B, Brandsdal, Bjørn O
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-06-2002
• Subjects: Animals; Computer Simulation; Humans; Ligands; Motion; Protein Binding; Proteins - chemistry; Thermodynamics
• ISSN: 0001-4842; 1520-4898
• DOI: 10.1021/ar010014p

Simplified free energy calculations based on force field energy estimates of ligand−receptor interactions and thermal conformational sampling have emerged as a useful tool in structure-based ligand design. Here we give an overview of the linear interaction energy (LIE) method for calculating ligand binding free energies from molecular dynamics simulations. A notable feature is that the binding energetics can be predicted by considering only the intermolecular interactions of the ligand in the associated and dissociated states. The approximations behind this approach are examined, and different parametrizations of the model are discussed. LIE-type methods appear particularly promising for computational “lead optimization”. Recent applications to protein−protein interactions and ion channel blocking are also discussed.