[32] Molecular modeling of ligand-gated ion channels

Molecular modeling is a method for mimicking the behavior of molecules and molecular systems. Simple molecular modeling studies can be performed using mechanical models. However, molecular modeling has now become synonymous with computer modeling. Computer-based molecular models are three dimensional in nature and are interactive. In the past, molecular modeling was restricted to a small cohort of people who wrote their own programs and managed their own computer systems. Computer workstations today are much more powerful than the mainframe computers of even several years ago and are relatively inexpensive. Software can be obtained readily from commercial companies, from academic laboratories, or via the World Wide Web (WWW). Molecular modeling produces testable hypotheses. These can be extremely useful, as in successfully predicting the structure of human immunodeficiency virus (HIV) protease. They can, however, lead one astray, as in our modeling of the guanosine triphosphate (GTP) versus guanosine diphosphate (GDP) bound forms of a GTP binding protein, Cdc42Hs; nevertheless, some aspects of this modeling study proved useful. Molecular modeling is particularly powerful when used as part of a multidisciplinary study in an iterative modeling/experimental verification cycle. This chapter discusses the way such techniques can be applied to ligand-gated ion channels, using efforts to model ionotropic glutamate receptors as an example.