Sigma conotoxin GVIIIA: Binding to 5HT3A with microsecond simulations and docking of diverse structures.

Abstract

The 5HT3A receptor is an important neurological receptor that can be inhibited by conotoxins from cone snails. It is therefore important to understand the significance of the toxin in terms of the structure function relationship and potentially prove that a diverse set of structures can inhibit the receptor. Long time scale simulations were run for several microseconds to observe unbiased binding of the toxin to the receptor. An important factor to consider with the docking is that the binding was only observed to occur from the membrane to the receptor and not from the aqueous phase to the receptor. The final structure of the unbiased binding to the receptor was saved and used to test other predicted disulfide bond configurations of the GVIIIA toxin structure. It is important to sample varied possible structures because protein prediction software are not perfect and certain structures might cause inhibitory effects to 5HT3A, which can be tested with ClusPro clustering software. The PMF of the unbiased and relaxed docked structure will be compared with each other to show if similar results can be obtained. Certain positions are more likely to occur than others because if our unbiased simulations are valid, the peptide needs to start from the membrane and transition to the receptor binding site. The project seeks to probe how much tolerance there is in the structure of the natural toxin peptides, and this could be an important consideration for future therapeutic and toxin development for a variety of applications.