Molecular determinants of ion channel chemical modulation
My bio-related research mainly surrounds computational investigation of ion channel proteins and their potential in oncogenic processes. I use a combination of abductive and computational structural biology methods (mostly molecular dynamics) to inquire into the atomic mechanisms of protein dynamics and modulation.
In the past, I used molecular dynamics (MD) simulations to investigate the binding pockets of the hEag1 ion channel. At the time, the 3D structures of the hEag1 and the related hERG channel had not yet been discovered and homology models based on bacterial templates were employed. The results led to identifying a particular structural feature in the S5-P region, which may be targeted by blockers with selective affinity (hERG and hEag1) with anti-cancer potential. More specifically, it was theorized that derivatives of a well-studied class III antiarrhythmic agent, clofilium, would have beneficial anti-cancer effects.
The research continued by overviewing the hERG ion channel based on novel cryo-EM structure and analyzing the high-affinity block by clofilium, the potent antiarrhythmic agent. MD simulations revealed a novel blocking mode and pinpointed a pattern relating hERG blocker affinity to determinant in the lower part of the channel inner pore. I currently look after furthering a more complete view on blocker selective affinity towards EAG channels. I also envision to build a unified view of two-pore domain (K2P) TWIK-related acid sensitive (TASK) channels and their implications and pathways in cancer cells. At the same time, I did some full MD simulations on TRPM8-ligand systems, to expand my research into calcium channels.
Publications
Șterbuleac D. and Maniu C.L. (2018) Computer Simulations Reveal a Novel Blocking Mode of the hERG Ion Channel by the Antiarrhythmic Agent Clofilium, Molecular Informatics, 37(6-7), 1700142 [link]
Șterbuleac D. and Maniu C.L. (2016) An antiarrhythmic agent as a promising lead compound for targeting the hEAG1 ion channel in cancer therapy: insights from molecular dynamics simulations, Chemical Biology and Drug Design, 88(5), 683-689 [link]
Reviewing the knowledge in the field
I have also devoted time to researching and organizing the knowledge in the field. My record includes, at the moment, two review papers focusing on (1) the chemical modulation of K2P channels and (2) the MD toolbox as applied on ion channels. The former is a state-of-the-art reorganization of the knowledge, and has been cited in Nature.
Publications
Șterbuleac D. (2021) Molecular dynamics: a powerful tool for studying the medicinal chemistry of ion channel modulators, RSC Medicinal Chemistry, 12, 1503-1518 [link]
Șterbuleac D. (2019) Molecular determinants of chemical modulation of two-pore domain potassium channels, Chemical Biology & Drug Design, 94(3), 1596-1614 [link]
MD-based investigations of other disease-relevant mutant protein dynamics
I seek to expand the applicability of the MD toolbox on various proteins and their mutant variants. I collaboratively pinpointed the differential dynamics of a disease-enhancing mutation in the SARS-CoV-2 accessory protein ORF7a. The A105V mutation induces peculiar changes in ORF7a dynamics, respective not to the per-residue root mean square deviation, but rather by deterministically diminishing the potential dynamic behavior in specific solvent-accessible loops. Given the detrimental role of this accessory protein in SARS-CoV-2 pathogenesis (revealed one piece of a puzzle at a time), the clinical results complemented by MD-based insights may aid our understanding of the unusual COVID-19 viral mechanisms.
Publications
Lobiuc, A.; Șterbuleac, D.; Sturdza, O.; Dimian, M.; Covasa, M. (2021) A Conservative Replacement in the Transmembrane Domain of SARS-CoV-2 ORF7a as a Putative Risk Factor in COVID-19. Biology, 10, 1276 [link]
Conceptualizing the Eco-Consortium – for environmental education in Academic settings
I collaboratively published two papers conceptualizing the Academic Environmental Organization and discussing Academic Eco-Consortia as a driver of change and student development in ecological and environmental-related fields.
Publications
Șterbuleac D. and Toma O. (2020) Environmental education through a University Eco-Consortium, Applied Environmental Education & Communication, 19(1), 62-73 [link]
Șterbuleac D. and Toma O. (2019) The overlooked role of academic environmental organizations in addressing environmental education issues, Applied Environmental Education & Communication, 18(1), 91-94 [link]
On-line profiles
Also check my full publication and list of on-line scientific profiles here.
Daniel Șterbuleac 