Making virtual seem more real
New method for molecular dynamics simulation developed
The Molecular Simulation Laboratory at ITQB has devised a new computational method to study the behaviour of redox proteins. Unlike previously available strategies, the method now published in the Journal of the American Chemical Society is able to deal with conformational and redox state changes at the same time, making the simulation of protein dynamics come closer to reality.
In living organisms, redox proteins play many and varied roles, ranging from enzyme catalysis to the energy transduction taking place in respiration. The hallmark of redox proteins is their ability to capture and release electrons in order to achieve their biological function. Their detailed experimental characterization involves determining how easily they capture or release electrons, namely by performing a redox titration - a process where the uptake of electrons is measured as a function of the reduction potential of the environment. This reduction potential measures the availability of electrons in the environment, just like the pH measures the availability of hydrogen ions, and is therefore a crucial experimental parameter in studying redox proteins.
Doing molecular simulations is like performing virtual experiments. By making atoms and molecules in the computer models obey to known physical laws, simulations allow researchers to see how molecules change over time in a given set of conditions. But, in the case of redox proteins, the existing methods were not fully satisfactory in the way they reflected the reduction potential of the environment. By extending some of their previous methods designed to better treat pH effects in molecular simulations, ITQB researchers were able to devise a novel approach where several protein properties can change over time during a computer simulation: the conformation, the redox state, and also the protonation state of the titrable aminoacids (histidines, glutamates, aspartates, etc). With this new approach, the behaviour of a redox protein can be simulated more realistically and comparisons with experimental data are made easier, since the simulation reflects directly the typical parameters of a redox process, such as temperature, pH, and reduction potential.
The published work applies this new approach to study the redox titration of cytochrome c3, a small redox protein involved in the respiration of Desulfovibrio vulgaris Hildenborough, a type of bacteria able to "breath" sulfate. The results of the computer simulations are in very good agreement with the experimental data available for this protein (also obtained at ITQB). The study also found that the protein can easily acommodate a temporary excess or deficit of electrons, which can be important for its role as an electron transporter. Given this good performance of the method and its generality, its application to other redox proteins is already being pursued. Overall, this work lays down a promising new route to study redox proteins using computer simulations, providing a complement or alternative to experimental studies.
Molecular Dynamics at Constant pH and Reduction Potential: Application to Cytochrome c3
Miguel Machuqueiro and António M. Baptista