PMID- 34214529
OWN - NLM
STAT- MEDLINE
DCOM- 20210811
LR  - 20220805
IS  - 1542-0086 (Electronic)
IS  - 0006-3495 (Print)
IS  - 0006-3495 (Linking)
VI  - 120
IP  - 15
DP  - 2021 Aug 3
TI  - Free energy and kinetics of cAMP permeation through connexin26 via applied 
      voltage and milestoning.
PG  - 2969-2983
LID - S0006-3495(21)00511-7 [pii]
LID - 10.1016/j.bpj.2021.06.024 [doi]
AB  - The connexin family is a diverse group of highly regulated wide-pore channels 
      permeable to biological signaling molecules. Despite the critical roles of 
      connexins in mediating selective molecular signaling in health and disease, the 
      basis of molecular permeation through these pores remains unclear. Here, we 
      report the thermodynamics and kinetics of binding and transport of a second 
      messenger, adenosine-3',5'-cyclophosphate (cAMP), through a connexin26 
      hemichannel (Cx26). First, inward and outward fluxes of cAMP molecules solvated 
      in KCl solution were obtained from 4 mus of +/- 200 mV simulations. These fluxes 
      data yielded a single-channel permeability of cAMP and cAMP/K(+) permeability 
      ratio consistent with experimentally measured values. The results from voltage 
      simulations were then compared with the potential of mean force (PMF) and the 
      mean first passage times (MFPTs) of a single cAMP without voltage, obtained from 
      a total of 16.5 mus of Voronoi-tessellated Markovian milestoning simulations. Both 
      the voltage simulations and the milestoning simulations revealed two cAMP-binding 
      sites, for which the binding constants K(D) and dissociation rates k(off) were 
      computed from PMF and MFPTs. The protein dipole inside the pore produces an 
      asymmetric PMF, reflected in unequal cAMP MFPTs in each direction once within the 
      pore. The free energy profiles under opposite voltages were derived from the 
      milestoning PMF and revealed the interplay between voltage and channel polarity 
      on the total free energy. In addition, we show how these factors influence the 
      cAMP dipole vector during permeation, and how cAMP affects the local and nonlocal 
      pore diameter in a position-dependent manner.
CI  - Copyright (c) 2021 Biophysical Society. Published by Elsevier Inc. All rights 
      reserved.
FAU - Jiang, Wenjuan
AU  - Jiang W
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Western University of 
      Health Sciences, Pomona, California.
FAU - Lin, Yi-Chun
AU  - Lin YC
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Western University of 
      Health Sciences, Pomona, California.
FAU - Botello-Smith, Wesley
AU  - Botello-Smith W
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Western University of 
      Health Sciences, Pomona, California.
FAU - Contreras, Jorge E
AU  - Contreras JE
AD  - Department of Physiology and Membrane Biology, School of Medicine, University of 
      California, Davis, California. Electronic address: jecontrer@ucdavis.edu.
FAU - Harris, Andrew L
AU  - Harris AL
AD  - Department of Pharmacology, Physiology, and Neuroscience, New Jersey Medical 
      School, Rutgers, The State University of New Jersey, Newark, New Jersey. 
      Electronic address: aharris@njms.rutgers.edu.
FAU - Maragliano, Luca
AU  - Maragliano L
AD  - Department of Life and Environmental Sciences, Polytechnic University of Marche, 
      Ancona, Italy; Center for Synaptic Neuroscience and Technology, Italian Institute 
      of Technology, Genoa, Italy. Electronic address: Luca.Maragliano@iit.it.
FAU - Luo, Yun Lyna
AU  - Luo YL
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Western University of 
      Health Sciences, Pomona, California. Electronic address: luoy@westernu.edu.
LA  - eng
GR  - R01 GM116961/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20210630
PL  - United States
TA  - Biophys J
JT  - Biophysical journal
JID - 0370626
RN  - 0 (Connexins)
RN  - 127120-53-0 (Connexin 26)
SB  - IM
MH  - Biophysical Phenomena
MH  - Connexin 26
MH  - *Connexins
MH  - Kinetics
MH  - Thermodynamics
PMC - PMC8391066
EDAT- 2021/07/03 06:00
MHDA- 2021/08/12 06:00
PMCR- 2022/08/03
CRDT- 2021/07/02 20:11
PHST- 2021/01/13 00:00 [received]
PHST- 2021/04/08 00:00 [revised]
PHST- 2021/06/17 00:00 [accepted]
PHST- 2021/07/03 06:00 [pubmed]
PHST- 2021/08/12 06:00 [medline]
PHST- 2021/07/02 20:11 [entrez]
PHST- 2022/08/03 00:00 [pmc-release]
AID - S0006-3495(21)00511-7 [pii]
AID - 10.1016/j.bpj.2021.06.024 [doi]
PST - ppublish
SO  - Biophys J. 2021 Aug 3;120(15):2969-2983. doi: 10.1016/j.bpj.2021.06.024. Epub 
      2021 Jun 30.