To what extent naringenin binding and membrane depolarization shape mitoBK channel gating-A machine learning approach

PLoS Comput Biol. 2022 Jul 20;18(7):e1010315. doi: 10.1371/journal.pcbi.1010315. eCollection 2022 Jul.

Abstract

The large conductance voltage- and Ca2+-activated K+ channels from the inner mitochondrial membrane (mitoBK) are modulated by a number of factors. Among them flavanones, including naringenin (Nar), arise as a promising group of mitoBK channel regulators from a pharmacological point of view. It is well known that in the presence of Nar the open state probability (pop) of mitoBK channels significantly increases. Nevertheless, the molecular mechanism of the mitoBK-Nar interactions remains still unrevealed. It is also not known whether the effects of naringenin administration on conformational dynamics can resemble those which are exerted by the other channel-activating stimuli. In aim to answer this question, we examine whether the dwell-time series of mitoBK channels which were obtained at different voltages and Nar concentrations (yet allowing to reach comparable pops) are discernible by means of artificial intelligence methods, including k-NN and shapelet learning. The obtained results suggest that the structural complexity of the gating dynamics is shaped both by the interaction of channel gate with the voltage sensor (VSD) and the Nar-binding site. For a majority of data one can observe stimulus-specific patterns of channel gating. Shapelet algorithm allows to obtain better prediction accuracy in most cases. Probably, because it takes into account the complexity of local features of a given signal. About 30% of the analyzed time series do not sufficiently differ to unambiguously distinguish them from each other, which can be interpreted in terms of the existence of the common features of mitoBK channel gating regardless of the type of activating stimulus. There exist long-range mutual interactions between VSD and the Nar-coordination site that are responsible for higher levels of Nar-activation (Δpop) at deeply depolarized membranes. These intra-sensor interactions are anticipated to have an allosteric nature.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Artificial Intelligence
  • Calcium / metabolism
  • Flavanones* / pharmacology
  • Machine Learning
  • Potassium Channels, Calcium-Activated*

Substances

  • Flavanones
  • Potassium Channels, Calcium-Activated
  • naringenin
  • Calcium

Grants and funding

This research was funded by Lukasiewicz Research Network–Institute of Medical Technology and Equipment as part of a subsidy from the Ministry of Education and Science (https://www.itam.zabrze.pl), and the Silesian University of Technology grant for young researchers No. 04/040/BKM22/0216 to AWJ (statute project) (https://www.polsl.pl). Patch-clamp data were obtained as part of the grant number 2016/21/B/NZ1/02769 from National Science Center of Poland (to PB)(https://www.ncn.gov.pl/en). The computational power for the calculations presented in this study was funded by the grant number 2018/29/B/ST3/01892 (MRL) (https://www.ncn.gov.pl/en). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.