ABSTRACT The PI proposes a high-impact research project to use the power of computational studies to rationally design photocontrol of the function of the ubiquitous calcium messenger protein, calmodulin (CaM). CaM transduces calcium signals by binding calcium ions and then modifying its interactions with various target proteins, many of which are unable to bind calcium themselves. CaM interacts with over 300 proteins, thereby mediating many crucial processes such as inflammation, neuropathic pain, metabolism, apoptosis, muscle contraction, intracellular movement, short-term and long-term memory, nerve growth and the immune response. The photocontrol of its binding to target proteins can hence provide valuable photoregulation of important events in the cell and be used for the treatment of disorders related to these phenomena. The very limited current research into CaM photocontrol suffers from the huge drawback that photoswitches with the desired optical properties and optimal sites for photoswitch attachment are discovered experimentally through trial and error, which is inefficient in terms of time and resources. The PI proposes to overcome this drawback by using computational studies to establish fundamental microscopic understanding of the photocontrol of CaM-target binding, which can subsequently be combined with experiments to rationally design photocontrolled CaM. The goals of this proposal are: 1) Establish the microscopic mechanism of experimentally observed photocontrol of CaM binding to the M13 peptide, a fragment of skeletal muscle myosin light chain kinase; 2) Validate the accuracy of computational models and methodology for designing CaM photocontrol by comparison against available experimental data; and 3) Establish the guiding principles for the design of azobenzene-based photoswitches with desired thermal relaxation timescales and absorption properties in the protein environment. In the long run, this body of knowledge will lead to predictions of ways to achieve desired photocontrol of CaM binding to a variety of target proteins, which can be verified and implemented by experiments. The true power of computations can hence be fully utilized to solve pressing problems in the field of design of photocontrol of CaM-protein interactions and is an innovation in this field. In addition, this proposal will enhance the infrastructure of biomedical research and education at the State University of New York at Binghamton, introducing computational biophysics which is indispensable in modern biomedical research to students who would otherwise lack this exposure.