Absolute Binding Free Energy Calculations using Molecular Dynamics Simulations with Restraining Potentials

¹ University of Chicago
² Argonne National Laboratory

^* To whom correspondence should be addressed. E-mail: roux{at}uchicago.edu.

Submitted on March 1, 2006
Revised on April 13, 2006
Accepted on 27 June 2006

	Abstract

The absolute (standard) binding free energy of eight FK506-related ligands with FKBP12 is calculated using free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent. A number of features are implemented to improve the accuracy and enhance the convergence of the calculations. First, the absolute binding free energy is rigorously decomposed into sequential steps during which the ligand-surrounding interactions as well as various biasing potentials restraining the translation, orientation and conformation of the ligand are turned "on" and "off". Second, sampling of the ligand conformation is enforced by a restraining potential based on the root-mean-square deviation (RMSD) relative to the bound state conformation. The effect of all the restraining potentials is rigorously unbiased, and it is shown explicitly that the final results are independent of all artificial restraints. Third, the repulsive and dispersive free energy contribution arising from the Lennard-Jones interactions of the ligand with its surrounding (protein and solvent) is calculated using the Weeks Chandler Andersen (WCA) separation. This separation also improves convergence of the FEP/MD calculations. Fourth, to decrease the computational cost only a small number of atoms in the vicinity of the binding site are simulated explicitly while all the influence of the remaining atoms is incorporated implicitly using the Generalized Solvent Boundary Potential (GSBP) method. With GSBP, the size of the simulated FKBP12/ligand systems is significantly reduced, from about 25,000 to 2,500 atoms. The computations are very efficient and the statistical error is small (~1 kcal/mol). The calculated binding free energies are generally in good agreement with available experimental data and previous extensive calculations by Shirts and Pande (within ~2 kcal/mol). The present results indicate that a strategy based on FEP/MD simulations of a reduced GSBP atomic model sampled with conformational, translational and orientational restraining potentials can be computationally inexpensive and accurate.

Key Words: MD, binding, calculation, dynamics, energy, simulation

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