Ali Navid ^1* John R. Casey ^1* Brian J. Bennion ¹ Patrik D'haeseleer ² Jeffrey A. Kimbrel ¹ Gianna L. Marschmann ³

• ¹ Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory (DOE), Livermore, California, United States
• ² Computing Directorate, Lawrence Livermore National Laboratory, Livermore, United States
• ³ Ecology Department, Lawrence Berkeley National Laboratory, Berkeley, United States

Mechanistic, constraint-based models of microbial isolates or communities are a staple in the metabolic analysis toolbox, but predictions about microbe-microbe and microbe-environment interactions are only as good as the accuracy of transporter annotations. A number of hurdles stand in the way of comprehensive functional assignments for membrane transporters. These include general or non-specific substrate assignments, ambiguity in the localization, directionality and reversibility of a transporter, and the many-to-many mapping of substrates, transporters and genes. In this perspective, we summarize progress in both experimental and computational approaches used to determine the function of transporters and consider paths forward that integrate both. Investment in accurate, high-throughput functional characterization is needed to train the next generation of predictive tools toward genome-scale metabolic network reconstructions that better predict phenotypes and interactions. More reliable predictions in this domain will benefit fields ranging from personalized medicine to metabolic engineering to microbial ecology.