Abstract
Understanding the role of stability strengths and weaknesses in proteins is a key objective for rationalizing their dynamical and functional properties such as conformational changes, catalytic activity, and protein-protein and protein-ligand interactions. We present BRANEart, a new, fast and accurate method to evaluate the per-residue contributions to the overall stability of membrane proteins. It is based on an extended set of recently introduced statistical potentials derived from membrane protein structures, which better describe the stability properties of this class of proteins than standard potentials derived from globular proteins. We defined a per-residue membrane propensity index from combinations of these potentials, which can be used to identify residues which strongly contribute to the stability of the transmembrane region or which would, on the contrary, be more stable in extramembrane regions, or vice versa. Large-scale application to membrane and globular proteins sets and application to tests cases show excellent agreement with experimental data. BRANEart thus appears as a useful instrument to analyze in detail the overall stability properties of a target membrane protein, to position it relative to the lipid bilayer, and to rationally modify its biophysical characteristics and function. BRANEart can be freely accessed from http://babylone.3bio.ulb.ac.be/BRANEart.
Highlights
The broad family of integral membrane proteins provides indispensable components of living cells
The membrane protein data set Dmem comes directly from a recent study (Mbaye et al, 2019). It consists of 163 X-ray structures of integral membrane proteins that have been collected from the Protein Data Bank (PDB) (Berman et al, 2000)
We set up the BRANEart predictor, which predicts for each residue in a protein structure a membrane protein index MPr, defined as a linear combination of several types of statistical potential values, derived from either EM or TM regions of a set of membrane protein structures (DEmMem and DTmMem), as defined in Eqs 1–8
Summary
The broad family of integral membrane proteins provides indispensable components of living cells. EM domains in the cytosolic or extracellular medium resemble globular proteins as their surfaces are exposed to water, while residues embedded within the membrane are exposed to lipids and are characterized by an elevated hydrophobicity (Leman et al, 2018; Mbaye et al, 2019). Because of this mixed environment, the study of folding and stability of membrane proteins is very challenging and only few tools have been dedicated to investigate them
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