Development of a hybrid computational method for the study of large-scale conformational transitions in proteins

Resumen

In this work, we use classical molecular dynamics simulations and structurebased potentials to study large-scale conformational changes in proteins. We propose a computational scheme able to reproduce such motions within the current computational capabilities that can be used for free energy calculations. The interest of this investigation is both clinical and fundamental. On the one hand it contributes to the mechanistic understanding of the regulation of multidomain proteins whose dysregulation is associated to human cancer like in the case under study, the c-Abl protein kinase. On a more foundational front, this protocol provided us with the chance to investigate protein conformational changes ranging from angstroms to tenths of nanometers, rarely accessible to current average computational capabilities, reaching a closer depiction of protein dynamics and mechanicism at the mesoscopic scale. Proteins are a fundamental category of macromolecules within the realm of living matter. They are responsible of performing a plethora of functions that are indispensable to the life of cells and organisms. Among them, enzymes are catalyst proteins: they lower the activation energy of a specific biochemical reaction, increasing its rate without being consumed by it. For many enzymes, scientists were able to identify amino acids directly involved in catalytic activity (for an example, see [1]). This led to the notion of associating the phases of an enzyme¿s activity and regulation to specific structural conformations. Computational methods of atomistic resolution such as molecular dynamics (MD, [2, 3]) can be extremely valuable in characterizing these conformations and help to quantify the accessibility of the conformational states involved in enzymatic function.