# Molecular Modeling and Dynamics of a Complete Connexin-43 Gap Junction Channel in Various Phosphorylation States

## TL;DR

This paper presents a computational model of the Cx43 gap junction channel and shows how phosphorylation affects its structure and function.

## Contribution

A full-length computational model of the Cx43 gap junction channel and its dynamics in different phosphorylation states is presented.

## Key findings

- Increased phosphorylation of serine residues in the CTD leads to extended and flexible CTD conformations with greater solvent exposure.
- Pore narrowing and distinct gating states are linked to hydrophobic interactions between NTHs and TM2.

## Abstract

Gap junction channels, formed by the docking of two hemichannels
from adjacent cells, are essential for intercellular communication.
Connexin-43 (Cx43), the most widely expressed connexin, is critically
involved in numerous physiological processes. Phosphorylation of Cx43
is a key regulatory mechanism that influences all aspects of its function,
including trafficking, channel gating, and permeability. Here, we
report a full-length computational model of the dodecameric Cx43 gap
junction channel in double bilayers, including its intracellular loops
and cytoplasmic regulatory C-terminal domains (CTDs). Furthermore,
we performed all-atom molecular dynamics simulations of four systems
representing different phosphorylation states. Our results demonstrate
that increased phosphorylation of serine residues in the CTD induces
more extended and flexible CTD conformations with greater solvent
exposure, meanwhile narrowing the channel pore. Distinct gating states
are closely associated with hydrophobic interactions between the N-terminal
helices (NTHs) and transmembrane domain 2 (TM2). Unfolding of the
NTHs disrupts the interactions, leading to pore distortion and a transition
from the initial closed state to a more open conformation. These findings
provide novel insights into the structural dynamics and regulatory
mechanisms of the Cx43 gap junction channels.