RESUMEN
The diverse selection of targets in the CAPRI experiments provides grounds for determining the limits of our rigid-body docking program MolFit, and for extending it. We find that the sensitivity of MolFit is high, enabling it to produce reasonably accurate docking solutions when the structures undergo moderate local conformation changes upon complex formation or when the docked molecules are modeled. Yet the ranks of these solutions are sometimes too low to meet the requirements of CAPRI assessment. This indicates that the selectivity of MolFit, which was optimized for docking of unbound X-ray structures, and which relies on the availability of external data from biochemical and bioinformatic sources, needs readjustment in order to meet the challenges presented by NMR or modeled structures. A different challenge is presented by large global conformation changes such as movements of domains. We show that such changes can be accommodated within the rigid-body approximation by employing rigid multibody multistage docking procedures. We also address the difficulty of ranking results from 2-body and multibody docking scans in cases in which there are no external data favoring one option over the other.
Asunto(s)
Biología Computacional/métodos , Mapeo de Interacción de Proteínas/métodos , Proteómica/métodos , Algoritmos , Simulación por Computador , Cristalografía por Rayos X , Bases de Datos de Proteínas , Dimerización , Internet , Sustancias Macromoleculares , Modelos Moleculares , Modelos Estadísticos , Conformación Molecular , Mutación , Conformación Proteica , Pliegue de Proteína , Estructura Terciaria de Proteína , Reproducibilidad de los Resultados , Programas Informáticos , Electricidad Estática , Homología Estructural de Proteína , TermodinámicaRESUMEN
Kinetic analysis of the dynamics as measured in multiequilibria systems is readily attained by curve-fitting methodologies, a treatment that can accurately retrace the shape of the measured signal. Still, these reconstructions are not related to the detailed mechanism of the process. In this study we subjected multiple proton transfer reactions to rigorous kinetic analysis, which consists of solving a set of coupled-nonlinear differential rate equations. The manual analysis of such systems can be biased by the operator; thus the analysis calls for impartial corroboration. What is more, there is no assurance that such a complex system has a unique solution. In this study, we used the Genetic Algorithm to investigate whether the solution of the system will converge into a single global minimum in the multidimensional parameter space. The experimental system consisted of proton transfer between four proton-binding sites with seven independent adjustable parameters. The results of the search indicate that the solution is unique and all adjustable parameters converge into a single minimum in the multidimensional parameter space, thus corroborating the accuracy of the manual analysis.