Investigation of Retinal Energetics with Novel OPLS Force Fields Applied to a Full-Retinylidene SystemBiochemical Science and Bioengineering
- Mr. Kevin Nieves Pichardo
"Rhodopsin is a member of the large family of transmembrane proteins known as G protein-coupled receptors (GPCRs) and is frequently used in drug design to model GPCR activation and behavior. GCPRs are used in signaling, regulation, and sensing in many organisms, including humans, making them attractive pharmaceutical targets. Retinal is the light-sensitive cofactor of rhodopsin responsible for its activation during phototransduction; it is covalently bound at Lysine 296 via a Schiff base linkage. Because of the complexity of the retinal energy landscape and its importance in rhodopsin activation, the development of an accurate computational model for retinylidene is of great interest. Both quantum mechanical (QM) and molecular dynamical (MD) methods have been used to study rhodopsin and retinal, but previous research has been limited by its use of small model systems and generic force fields. This research improves upon previous studies by using novel, retinal-specific force fields applied to the entire retinylidene system. These force fields were derived using artificial intelligence algorithms which took Born-Oppenheimer Molecular Dynamics (BOMD) trajectories as inputs. MD simulations used the Optimized Potentials for Liquid Simulations (OPLS) functional form for its four dihedral torsional energy terms instead of the single-term description used by CHARMM and previous studies. These changes allow us to reproduce experimentally-determined C5, C9, and C13 rotation energies much more closely than previous studies. Our work highlights the need for molecule-specific force field parameterizations in order to correctly model GPCR activations."