ConfID: an analytical method for conformational characterization of small molecules using molecular dynamics trajectories

Motivation The conformational space of small molecules can be vast and difficult to assess. Molecular dynamics (MD) simulations of free ligands in solution have been applied to predict conformational populations, but their characterization is often based on clustering algorithms or manual efforts. Results Here, we introduce ConfID, an analytical tool for conformational characterization of small molecules using MD trajectories. The evolution of conformational sampling and population frequencies throughout trajectories is calculated to check for sampling convergence while allowing to map relevant conformational transitions. The tool is designed to track conformational transition events and calculate time-dependent properties for each conformational population detected. Availability and implementation Toolkit and documentation are freely available at http://sbcb.inf.ufrgs.br/confid Contact [email protected] or [email protected] Supplementary information Supplementary data are available at Bioinformatics online.

SpeciFlex: A Protocol for Mining Binding Site Conformational Selectivity in Structure-Based Inhibitor Discovery

Selectivity for a target site is challenging when the site is conserved in homologous proteins. A novel protocol is presented for attaining selectivity by taking advantage of conformational population differences between homologs. Conformational ensembles of the targeted protein and the homolog are compared to identify pockets significantly populated in the target, but rarely or never sampled in the homolog. SLIDE screening then identifies molecules that fit the unique pocket and also interact well with an adjacent substrate pocket. The SpeciFlex protocol, demonstrated for a pair of pyrophosphokinases, yields ligand candidates with good interactions in both the substrate and unique pockets of the target Yersinia pestis protein, while selecting against interactions with the homologous site in Escherichia coli.

Structural basis for a hand-like site in the calcium sensor CatchER with fast kinetics

Calcium ions, which are important signaling molecules, can be detected in the endoplasmic reticulum by an engineered mutant of green fluorescent protein (GFP) designated CatchER with a fast off-rate. High resolution (1.78–1.20 Å) crystal structures were analyzed for CatchER in the apo form and in complexes with calcium or gadolinium to probe the binding site for metal ions. While CatchER exhibits a 1:1 binding stoichiometry in solution, two positions were observed for each of the metal ions bound within the hand-like site formed by the carboxylate side chains of the mutated residues S147E, S202D, Q204E, F223E and T225E that may be responsible for its fast kinetic properties. Comparison of the structures of CatchER, wild-type GFP and enhanced GFP confirmed that different conformations of Thr203 and Glu222 are associated with the two forms of Tyr66 of the chromophore which are responsible for the absorbance wavelengths of the different proteins. Calcium binding to CatchER may shift the equilibrium for conformational population of the Glu222 side chain and lead to further changes in its optical properties.