A Continuum Poisson-Boltzmann Model for Membrane Channel Proteins

TL;DR

This paper introduces a refined continuum Poisson-Boltzmann model for membrane channel proteins, improving accuracy in water distribution and pore identification, validated through binding affinity calculations matching experimental data.

Contribution

The paper presents a novel continuum membrane model with optimized parameters and automatic pore detection, enhancing computational studies of membrane proteins over previous models.

Findings

Optimized membrane model reproduces water distributions from explicit simulations.

Water probe of 1.4 Å is suitable for membrane protein simulations.

Model accurately predicts binding affinity for a potassium channel.

Abstract

Membrane proteins constitute a large portion of the human proteome and perform a variety of important functions as membrane receptors, transport proteins, enzymes, signaling proteins, and more. The computational studies of membrane proteins are usually much more complicated than those of globular proteins. Here we propose a new continuum model for Poisson-Boltzmann calculations of membrane channel proteins. Major improvements over the existing continuum slab model are as follows: 1) The location and thickness of the slab model are fine-tuned based on explicit-solvent MD simulations. 2) The highly different accessibility in the membrane and water regions are addressed with a two-step, two-probe grid labeling procedure, and 3) The water pores/channels are automatically identified. The new continuum membrane model is optimized (by adjusting the membrane probe, as well as the slab thickness and center) to best reproduce the distributions of buried water molecules in the membrane region as sampled in explicit water simulations. Our optimization also shows that the widely adopted water probe of 1.4 {\AA} for globular proteins is a very reasonable default value for membrane protein simulations. It gives an overall minimum number of inconsistencies between the continuum and explicit representations of water distributions in membrane channel proteins, at least in the water accessible pore/channel regions that we focus on. Finally, we validate the new membrane model by carrying out binding affinity calculations for a potassium channel, and we observe a good agreement with experiment results.