Calculation of Absolute Protein-Ligand Binding Affinity using Path and Endpoint Approaches

¹ U. S. Army Research Laboratory
² U. S. Army Medical Research Institute of Infectious Diseases

^* To whom correspondence should be addressed. E-mail: michael.lee{at}amedd.army.mil.

Submitted on July 28, 2005
Revised on September 19, 2005
Accepted on 20 October 2005

	Abstract

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.

Key Words: binding affinity, generalized Born, implicit solvent, molecular dynamics, potential of mean force, protein-ligand complex

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