The study led by Jeffery Klauda, a professor of Chemical and Biomolecular Engineering (ChBE) at the University of Maryland (UMD), has been published in theProceedings of the National Academy of Sciences(PNAS). Nicholas Guros, a ChBE graduate research assistant, served as first author on the study and was co-advised by Arvind Balijepalli, a mechanical engineer at NIST.
5HT3Ais a type of protein known as an ion channel, implicated in depression, anxiety and targeted to reduce chemotherapy-induced nausea. It regulates the flow of ions at the post-synaptic cleft of neurons. The authors performed computer simulations of 5HT3Afor up to 20 microseconds - much longer than past simulations performed.
"If you think of molecular dynamics (MD) as a molecular microscope, this means we're able to observe the mechanism of activation for 10x longer than past", stated Nicholas Guros. "New computational capabilities can provide the power to observe the molecular activation of complex proteins at significantly greater timescales. The longer this timescale, the better validation we can have of experimental results to demonstrate MD models are a robust method to study protein and test pharmaceuticals."
The activation and desensitization of proteins like 5HT3Aoccur over milliseconds, so while closer to the true timescale, scientists are still somewhat behind observing the entire transport cycle of the protein. This study, however, was able to provide insight into the effects of serotonin binding on developing a preactive state of 5HT3Aand how membrane lipids diversity influences protein structure and function.
Much simulation space to explore with these models remains, and it's only been made possible in the past few years with strides in computational power. Specifically, this study was performed using a grant-based allocation on the Anton2 supercomputer maintained by the Pittsburgh Supercomuting Center (PSC) and sponsored by DE Shaw research. Traditional high-performance computing resources would not be capable of reaching the timescales of this study.
As computing speed and power increases in the future, the group hopes to study the effects of pharmaceuticals, such as granisetron or ondansetron, in an effort to accurately model their effects on the protein and investigate other targeted therapies.
Guros, N.B., Balijepalli, A. and Klauda, J.B. are the authors of the paper titled " Microsecond Timescale Simulations Suggests 5-HT mediated Pre-activation of the 5-HT<sub>3A</sub> Serotonin Receptor ", published inProceedings of the National Academy of Sciences- DOI: 10.1073/pnas.1908848117.