# Role of Water Models in Simulations of Ion Conduction in Potassium Channels

## TL;DR

This paper investigates how different water models affect simulations of ion conduction in potassium channels, revealing that both hard and soft knock-on mechanisms can coexist and transition reversibly.

## Contribution

The study demonstrates that simulation parameters, particularly water models, significantly influence observed ion conduction mechanisms in potassium channels.

## Key findings

- Both hard and soft knock-on mechanisms are accessible and can reversibly transition in MthK and KcsA channels.
- The OPC water model allows coexistence of both mechanisms, unlike the TIP3P model which favors hard knock-on.
- Simulation parameters critically influence potassium channel permeation behavior and reconcile conflicting experimental observations.

## Abstract

Potassium channels exhibit high selectivity and conductance,
yet
the atomic details of ion permeation, particularly the involvement
of water molecules, remain debated. Two main conduction mechanisms
have been proposed: the hard knock-on, in which ions traverse the
selectivity filter in direct contact, and the soft knock-on, which
involves copermeation of water molecules. Using microsecond molecular
dynamics simulations with the OPC water model, the AMBER19SB protein
force field, and the 12–6–4 Sengupta et al. ion model,
and an analysis strategy based on Markov State Models, we observed
that both hard and soft knock-on mechanisms are accessible and, notably,
can reversibly transition in the MthK and KcsA channels across all
simulated membrane potentials. These reversible transitions contrast
with previous observations using the TIP3P water model, where water
entry either disrupted conduction or was expelled, favoring exclusive
hard knock-on events. Our results suggest that the choice of the water
model, force field, and ion parameters significantly influences the
observed conduction mechanism. Importantly, the coexistence of hard
and soft knock-on in these simulations provides a reconciliation between
structural data supporting hard knock-on and streaming potential measurements
demonstrating water copermeation. These findings reintroduce soft
knock-on as a viable conduction mechanism and highlight the critical
role of simulation parameters in reproducing potassium channel permeation
behavior.