Multiscale modeling of photo-active proteins

Light is an essential environmental stimulus in living organisms, and many species have evolved sensors to respond to it. Blue-light sensing proteins that use a flavin chromophore (BLUF) are members of a newly discovered receptor family that is widely distributed among microorganisms. The secondary structure of BLUF domains does not resemble that of other known receptors and spectroscopic experiments suggest a unique photochemistry, based on a change of redox potential at the chromophore and relatively small structural changes in the overall protein, although the underlying molecular mechanism remains to be resolved. Understanding these molecular aspects of the signal transduction in BLUF is the scientific theme of this proposal. Although molecular modelling methods and computing resources have advanced to the point that the dynamics of an aqueous protein can be simulated for some tens of nanoseconds, it is still a major challenge to model the complex chemical and structural rearrangements that make up the photocycle of a light receptor. In this project, this goal is achieved by combining state-of-the-art ab initio and molecular dynamics methods with new advanced simulation techniques. In particular, novel multi-scale methods allow for bridging otherwise prohibitively large time and length scales, while techniques that probe the free energy landscape will provide a unique insight in the microscopic reaction coordinate and the transition rates. In a broader view, the light-sensing BLUF domain is fully modular and can relay signals to structurally and functionally diverse output units. The proposed multiscale modelling approach will provide important microscopic insight into these generic modular interactions of signal transduction. With the iterative and complementary interaction with experimental groups, this approach has all the potential to set a new computational standard, applicable to numerous other biomolecular processes.