A membrane insertion code for intrinsically disordered proteins.

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• Membrane association of intrinsically disordered proteins (IDPs) is crucial for cellular functions like signal transduction.
• While mechanisms for helix and polybasic motif association are known, the sequence basis for aromatic residue membrane insertion remains unclear.

Purpose of the Study:

• To decipher the sequence determinants for deep membrane insertion of aromatic-centered motifs in IDPs.
• To develop a predictive model for the membrane insertion propensities of these motifs.

Main Methods:

• Utilized all-atom molecular dynamics simulations and the Positioning of Proteins in Membranes (PPM) method.
• Screened a large library of sequences (1.2 × 10^6) with varying aromatic residues and flanking amino acids.
• Developed the AroMIP mathematical model based on identified sequence rules.

Main Results:

• Identified that aliphatic (L) and basic (R) residues promote membrane insertion, while acidic (E) and polar (N) residues disfavor it.
• The AroMIP model accurately predicts membrane insertion propensities for F-, W-, and Y-centered motifs (>90% accuracy).
• A web server for AroMIP is publicly available for studying IDP-membrane association.

Conclusions:

• Established the sequence basis and mechanistic understanding of aromatic-centered motif-driven membrane insertion by IDPs.
• AroMIP provides a valuable tool for predicting and analyzing IDP-membrane interactions.
• This work enhances the study of diverse cellular functions mediated by IDP membrane association.