Our brains process information and make decisions in the form of electrical impulses. Being able to measure when neurons fire electrical impulses would allow us to understand how the brain carries out various functions, such as encoding sensations, recalling thoughts, or making decisions. Neuroscientists thus have long desired reliable ways to visualize electrical activity in neurons in real time. In this proposal, a computational biophysicist (Dror) and a protein engineer (Lin) will team up to improve voltage-sensing fluorescent proteins, proteins that can report electrical activity by changing their production of light. We will begin with ASAPs, a family of voltage indicators recently created by the Lin Lab. Dr. Dror has expertise in using physics-based computer simulations to understand how proteins move, including voltage- induced motions in voltage-sensing protein domains similar to the one that drives responses in ASAPs. We propose to use these simulations to study voltage-induced movements of ASAPs. By identifying what parts of the protein limit speed and responsiveness, we will generate new ideas for improving ASAP responses that we can immediately test. If successful, this collaborative interdisciplinary work can lead to dramatic improvements in voltage sensor performance, enabling the detection of faster or smaller electrical impulses than previously possible.