Journal of chemical information and modeling 2017 09 05() doi 10.1021/acs.jcim.7b00207
The protonation state of asp dyad is significantly important in revealing enzymatic mechanism and developing drugs. However, it is hard to be determined by calculating free energy changes between possible protonation states, because the free energy changes due to protein conformational flexibility are usually much larger than that originated from the different locations of protons. Sophisticated and computationally expensive methods such as free energy perturbation, thermodynamic integration, and QM/MM are therefore usually used for this purpose. In the present study, we have developed a simple thermodynamic approach to effectively eliminating the free energy changes arising from proteins conformational flexibility and estimating the free energy changes only originated from the locations of protons, which provides a fast and reliable method for determining the protonation state of asp dyad. The test of this approach on totally 15 asp dyad’s systems, including BACE-1 and HIV-1 protease, shows that the predictions from this approach are all consistent with experiments or with the computationally expensive TI calculations. It is clear that our thermodynamic approach could be used to rapidly and reliably determine the protonation state of asp dyad.