Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, understanding how 7TMRs function is an important goal of biomedical research. We continue to apply molecular modeling approaches to the study of the molecular details of ligand binding to 7TMRs and to the mechanism of activation of these receptors. We study receptors for thyrotropin-releasing hormone (TRH) (TRH-Rs), for thyroid-stimulating hormone (TSH-R) and for free fatty acids (GPR40/FFAR1) as model 7TMRs. During this year, we studied several aspects of binding of low molecular weight (LMW) ligands and of free fatty acids to FFAR1 and used novel molecular models of the FFAR1 in an iterative fashion with experiments to better define the FFAR1 binding cavity. Based on insights gained from these molecular models, we decided to attempt to develop a kinetic model for activation of rhodopsin, a much better-studied GPCR for which crystal structures of several intermediates have been resolved. We developed such a model that predicts a series of conformations that that are concordant with the known intermediates and predicts the molecular details of these transitions and predicts the active state conformation.