The Molecular Modeling Core enjoys a long-standing collaboration with Dr. Robert Guys section in the Lab of Cell Biology. We have taken an evolutionary approach to the study of ion channel proteins, examining the structural changes that accompanied the development of Na+ and Ca2+ channels from K+ channels by making representative models of each subfamily. In this pursuit, we have recently published models of the prokaryotic NaChBac channel, which is an evolutionary link between the ancestor K+ channels and the descendent Na+ and Ca2+ channels. The models explain the delicate balance of amino acid residue types in the pore that determine the specific ion selectivity, and the coupling of the voltage-sensor and activation gate. We are now using these results as a stepping stone to model the more complex eukaryotic Na+ and Ca2+ channels. In collaboration with experimental groups, we will be using these models to analyze the molecular pharmacology of Ca2+ channel blockers (important in treating hypertension and heart disease in humans and potentially as antifungicides) and to better understand how mutations associated with genetic diseases alter the gating properties of Ca2+ channels. Recently, we have also revisited our past work modeling the ion channel structures formed by the Amyloid-Beta Peptide (ABP) associated with Alzheimers disease. While it used to be thought that Alzheimers was caused by large fibril structures, numerous recent studies now indicate that the inhibition of long-term potentiation responsible for short-term memory loss and the neurotoxicity responsible for cell death are due to smaller oligomeric assemblies of the peptides. Recent studies also indicate and confirm that the neurotoxity involves interactions of the oligomers with membranes and that ABP indeed forms transmembrane ion channels. Unfortunately, however, direct experimental determination has been hampered by the fact that both aqueous and membrane-bound oligomeric structures of ABP are very sensitive to the specifics of the environment, and change over time. Consequently, we have updated our modeling of ABP structures by combining all the recent experimental data with computational molecular modeling techniques. We are about ready to publish two papers that trace the development of both long fibrils and ion channel structures from the smallest associations of aqueous-soluble and membrane-bound ABP. We will now explore how these models can help design modified peptides to form more stable assemblies for structure determination, and how they can serve as targets for drug design. We have also been modeling structures of the Prion Protein (PrP), which has segments of amino acid sequence similar to ABP. These models are intended to help pharmaceutical development to combat the spongiform encephalopathies caused by PrP.
| Arispe, Nelson; Diaz, Juan; Durell, Stewart R et al. (2010) Polyhistidine peptide inhibitor of the Abeta calcium channel potently blocks the Abeta-induced calcium response in cells. Theoretical modeling suggests a cooperative binding process. Biochemistry 49:7847-53 |
