DTIC ADA449444: Calculation of Absolute Protein Ligand pdf

DTIC ADA449444: Calculation of Absolute Protein Ligand

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A comparative analysis is provided of rigorous and approximate methods for calculating absolute binding affinities of two protein-ligand complexes: the FKBP protein bound with small molecules BUQ and FK506. Our rigorous approach is an umbrella sampling technique where a potential of mean force is determined by pulling the ligand out of the protein active site over several simulation windows. The results of this approach agree well with experimentally observed binding affinities. Also assessed is a commonly used approximate endpoint approach, which separately estimates enthalpy, solvation free energy, and entropy. We show that this endpoint approach has numerous variations, all of which are prone to critical shortcomings. For example, conventional harmonic and quasi-harmonic entropy estimation procedures produce disparate results for the relatively simple protein-ligand systems studied in this work

• Creator/s: Defense Technical Information Center
• Date: 2/1/2006
• Year: 2006
• Book Topics/Themes: DTIC Archive, Lee, Michael S, ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD, *PROTEINS, *LIGANDS, *RECEPTOR SITES(PHYSIOLOGY), COMPUTERIZED SIMULATION, SOLVATION, ENTROPY, POISSON EQUATION, ENTHALPY, SAMPLING, REPRINTS

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