Proton Paths in Models of the Hv1 Proton Channel

Area of Science:

• Molecular biology
• Biophysics
• Computational chemistry

Background:

• The voltage-gated proton channel (Hv1) is crucial for many biological functions, but its molecular mechanisms remain poorly understood.
• Existing structural models for Hv1's open and resting states are limited and their validity is uncertain.
• Disagreements persist regarding proton translocation pathways, the roles of specific amino acid residues, and pH-dependent gating.

Purpose of the Study:

• To evaluate proposed structural models of the voltage-gated proton channel (Hv1) using computational simulations.
• To investigate the mechanism of proton conduction through Hv1.
• To explore the role of specific residues and salt bridges in Hv1 function.

Main Methods:

• Classical proton hopping simulations were employed under voltage-biased conditions.
• Multiple structural models for Hv1, including those with different salt bridge configurations (D112-R211 and D112-R208), were simulated.
• Simulations included a negative control using a non-proton-conducting Kv1.2-Kv2.1 paddle-chimera voltage sensor.

Main Results:

• Paradoxically, some models proposed for the closed state exhibited higher proton permeation than open-state models.
• The D112-R211 salt bridge model (R3D) showed higher proton transport than the D112-R208 model (R2D), though potentially too high compared to experimental data.
• Protons were observed to permeate through a water wire, bypassing D112, which is stabilized by an arginine residue, preventing its protonation and direct involvement in proton shuttling.

Conclusions:

• The study provides insights into the proton conduction mechanism of Hv1, highlighting the role of a water wire and the importance of salt bridge interactions.
• Certain structural models, particularly those for the closed state, may better represent proton permeation pathways.
• The findings challenge previous assumptions about the direct role of D112 in proton translocation and emphasize the influence of arginine interactions on channel gating and selectivity.