Membrane Protein Properties Revealed through Data-Rich Electrostatics Calculations

Abstract

SUMMARY The electrostatic properties of membrane proteins often reveal many of their key biophysical characteristics, such as ion channel selectivity and the stability of charged membrane-spanning segments. The Poisson-Boltzmann (PB) equation is the gold standard for calculating protein electrostatics, and the software APBSmem enables the solution of the PB equation in the presence of a membrane. Here, we describe significant advances to APBSmem including: full automation of system setup, per-residue energy decomposition, incorporation of PDB2PQR, calculation of membrane induced pKa shifts, calculation of non-polar energies, and command-line scripting for large scale calculations. We highlight these new features with calculations carried out on a number of membrane proteins, including the recently solved structure of the ion channel TRPV1 and a large survey of 1,614 membrane proteins of known structure. This survey provides a comprehensive list of residues with large electrostatic penalties for being embedded in the membrane potentially revealing interesting functional information.

A lower affinity to cytosolic proteins reveals VDAC3 isoform-specific role in mitochondrial biology

“…APBSmem (Callenberg et al, 2010) was used to carry out electrostatic calculations and ion permeation profiles on the mVDAC1 structure (3EMN) and the hVDAC3 model, obtained using the SWISS-MODEL server (https://swissmodel.expasy.org/; Bordoli et al, 2009). All calculations were performed as previously described (Marcoline et al, 2015) using a 161 × 161 × 161 grid dual level focusing. The influence of the membrane was included as a low-dielectric slab (ε = 2) with headgroup and water assigned a polar dielectric value (ε = 80).…”

Continuum descriptions of membranes and their interaction with proteins: Towards chemically accurate models

“…We first solve for a given membrane deformation and then feed the shape of the solution into a continuum Poisson-Boltzmann electrostatic solver [133] by ‘painting’ the new dielectric environment around the protein [128]. Electrostatic considerations are crucial due to the low-dielectric environment of the membrane core, which poses a barrier to charged moieties on the protein, and computationally the protein, membrane, and aqueous solution are all given distinct dielectric values and solved easily with the numeric software APBS or APBSmem [134–136]. One of the most important driving forces for protein association with the membrane is the hydrophobic effect or non-polar solvation energy.…”

Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC)

“…Ensemble-wide MD simulations with applied electrical field remain rather rare because of the computational burden. A viable strategy could be based on application of continuum electrostatic modelling [83], Poisson-Nernst-Plank (PNP) electro-diffusion theory, or more detailed approaches based on Brownian Dynamics (BD) simulations [1]. They are considerably less costly and may be a practical alternative for large channels such as VDAC.…”