Thermodynamic integration to predict host-guest binding affinities |
| |
Authors: | Morgan Lawrenz Jeff Wereszczynski Juan Manuel Ortiz-Sánchez Sara E Nichols J Andrew McCammon |
| |
Institution: | Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, CA, USA. mlawrenz@ucsd.edu |
| |
Abstract: | An alchemical free energy method with explicit solvent molecular dynamics simulations was applied as part of the blind prediction contest SAMPL3 to calculate binding free energies for seven guests to an acyclic cucurbit-n]uril host. The predictions included determination of protonation states for both host and guests, docking pose generation, and binding free energy calculations using thermodynamic integration. We found a root mean square error (RMSE) of 3.6 kcal mol(-1) from the reference experimental results, with an R(2) correlation of 0.51. The agreement with experiment for the largest contributor to this error, guest 6, is improved by 1.7 kcal mol(-1) when a periodicity-induced free energy correction is applied. The corrections for the other ligands were significantly smaller, and altogether the RMSE was reduced by 0.4 kcal mol(-1). We link properties of the host-guest systems during simulation to errors in the computed free energies. Overall, we show that charged host-guest systems studied here, initialized in unconfirmed docking poses, present a challenge to accurate alchemical simulation methods. |
| |
Keywords: | |
本文献已被 PubMed SpringerLink 等数据库收录! |
|