Automated Large-Scale File Preparation, Docking, and Scoring: Evaluation of ITScore and STScore Using the 2012 Community Structure–Activity Resource Benchmark

In this study, we use the recently released 2012 Community Structure–Activity Resource (CSAR) data set to evaluate two knowledge-based scoring functions, ITScore and STScore, and a simple force-field-based potential (VDWScore). The CSAR data set contains 757 compounds, most with known affinities, and 57 crystal structures. With the help of the script files for docking preparation, we use the full CSAR data set to evaluate the performances of the scoring functions on binding affinity prediction and active/inactive compound discrimination. The CSAR subset that includes crystal structures is used as well, to evaluate the performances of the scoring functions on binding mode and affinity predictions. Within this structure subset, we investigate the importance of accurate ligand and protein conformational sampling and find that the binding affinity predictions are less sensitive to non-native ligand and protein conformations than the binding mode predictions. We also find the full CSAR data set to be more challenging in making binding mode predictions than the subset with structures. The script files used for preparing the CSAR data set for docking, including scripts for canonicalization of the ligand atoms, are offered freely to the academic community

Computation and Simulation of the Structural Characteristics of the Kidney Urea Transporter and Behaviors of Urea Transport

Urea transporters are a family of membrane proteins that transport urea molecules across cell membranes and play important roles in a variety of physiological processes. Although the crystal structure of bacterial urea channel <i>dv</i>UT has been solved, there lacks an understanding of the dynamics of urea transport in <i>dv</i>UT. In this study, by using molecular dynamics simulations, Monte Carlo methods, and the adaptive biasing force approach, we built the equilibrium structure of <i>dv</i>UT, calculated the variation in the free energy of urea, determined the urea-binding sites of <i>dv</i>UT, gained insight into the microscopic process of urea transport, and studied the water permeability in <i>dv</i>UT including the analysis of a water chain in the pore. The strategy used in this work can be applied to studying transport behaviors of other membrane proteins