Modeling Ion Channel Conductance
Location(s): United States
Ion channels mediate and regulate transport of charged species across cell membranes. Not only do they play an essential role in the physiology of a cell but are also frequent drug targets. Despite their importance in biology and medicine, we know less about them than about nearly any other major class of proteins. Only in the last decade were high-resolution structures of a number of ion channels solved through x-ray crystallography. However, a considerable gap still remains in understanding the structure-function relationship, as information revealed by x-ray crystallography is static and often incomplete. Model building and molecular dynamics (MD) simulations combined with x-ray structures can, in principle, help close this gap by providing insight into the dynamics of functional states and processes associated with ion conductance.
To determine the relevance of MD simulations, they should be compared with experimental electrophysiological data, which directly measure the main function of ion channels—ionic conductance. At present, such comparisons are very difficult to perform for large, eukaryotic ion channels or their bacterial homologs, as they require long simulations, most likely extending to multi-microsecond timescales. Instead, we can test the approach and improve the computational tools using simple model channels. These channels not only inform us about how complex channels function, but also are of considerable interest in their own rights. Some are viral channels which are promising drug targets (3). Others, formed by nongenomic proteins from higher organisms, are themselves therapeutic, because they exhibit antimicrobial activity.
In this study, we focus on ion channels formed by antiamoebin 1 (AAM), a member of a nonribosomally synthesized family of fungal peptides called peptaibols