 Sugar porters, SPS, are a large family of secondary active transporters that play important roles in maintaining blood glucose levels in mammals. Co-evolution analysis and comparative modelling were used to predict structures of SPS in various states of the transport cycle, including those involved in proton coupling. The resulting free energy landscape was consistent with experimental data, providing insight into the molecular determinants of the transport cycle. This work has implications for understanding the evolutionary origins of proton coupling and provides a framework for studying other protein families. This article was offered by Darko Mitrovich, Sarah E. McComas, Claudia Oliva, and others.