Design principles for K+ selectivity in membrane transport

Selection among competing alternatives is always interesting, but when organisms select between K+ and Na+ for transport across biological membranes, it is especially intriguing for a couple of reasons (Hille, 2001). First, the results are physiologically significant. Second, K+ and Na+ are nearly as similar as they could be while not being the same things. Perhaps the separation of isotopes of the same chemical species is more demanding. Despite decades of research, the question remains: how do K+-selective ion channels catalyze K+ movement but recognize the detailed molecular-scale differences of Na+ and discriminate against it? Suggestions based on channel size and coordination chemistry (Bezanilla and Armstrong, 1972; Eisenman and Horn, 1983) have been available for a long time, but the determination of a KcsA K+ channel crystal structure (Doyle et al., 1998) enabled molecularly specific modeling studies of this K+/Na+ selectivity. In the subsequent flood of computational studies, finding consistency in results and interpretations has proven challenging. Here, we describe our perspective on how molecular modeling has advanced our understanding of the specific chemical and structural design elements of biological molecules that enable selective ion transport.