Lipid-driven alignment and binding of p7 dimers in early oligomer assembly
Oluwatoyin Campbell, Dina Dahhan, Viviana Monje
Abstract
Proteins interact with lipid membranes to facilitate important cellular processes that underlie health and disease. Transmembrane proteins like ion channels are often composed of bound monomers forming specific contacts within the bilayer. However, molecular mechanisms of channel assembly are scarce. Understanding the role of lipids in this process may help further explain assembly of oligomeric proteins, which are often clinical drug targets.
Introduction
Protein and lipid interactions are fundamental contributors to cellular processes in health and disease. Lipid structural and compositional diversity in cell membranes provide a platform for protein interactions which underlie their function [1]. This involves changes to the structure of both proteins and lipids, which leads to the alteration of the surrounding lipid content near the protein and formation of sub-domains of different physical properties in the membrane [2–6].
Materials and methods
To probe the effect of lipid composition on dimerization of p7 monomers, three different models were simulated: (i) the monomers initially separated in water (Sep model), (ii) a control system containing two monomers in water in the experimentally determined channel conformation from PDBID 2M6X (Bound model), and (iii) the monomers initially separated on the surface of an anionic-charged membrane (Surface model).
Results
Dimer conformational changes are mediated by membrane lipids
After simulations were completed, the structural and conformational changes within the monomers were first evaluated. The Sep and Surface model systems (Fig 1) equilibrated within the first half of the respective trajectory, as seen from the root mean square deviation (RMSD) time series of monomer 1 and monomer 2 (referred to as p1 and p2 in S3A and S3B Fig), which also exhibit converged RMSF profiles for most replicas (S4 Fig).
Discussion
Protein assembly mechanisms of transmembrane channels remain underexplained for the most part. This stems from existing challenges in examining the dynamic changes of membrane protein structures at high resolution. Vesicles and lipid detergents used in experimental investigations are often limited to simple mixtures of membrane lipids compared to more complex models of the diverse lipidome of cells [56].
Acknowledgments
This work was performed on the University at Buffalo’s Center for Computational Research (Center for Computational Research, 2019).
Citation: Campbell O, Dahhan D, Monje V (2025) Lipid-driven alignment and binding of p7 dimers in early oligomer assembly. PLoS Comput Biol 21(11): e1013736. https://doi.org/10.1371/journal.pcbi.1013736
Editor: Alexander MacKerell, University of Maryland School of Pharmacy, UNITED STATES OF AMERICA
Received: July 29, 2025; Accepted: November 13, 2025; Published: November 25, 2025
Copyright: © 2025 Campbell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Final system coordinates, topology, and trajectory files are available at [https://zenodo.org/records/17645516]. Python, Bash and TCL analysis scripts used to calculate helicity, frequency of residue-lipid contacts and hydrogen bonds, tilt angle conformational landscapes, dynamic cross correlations and binding free energies are publicly available at https://github.com/monjegroup/p7-dimer.
Funding: The authors thank the Graduate Women in Science for funding support of the research of O.C.’s through the Nell I. Mondy Fellowship, which was used to support the training and work of D.D. towards this project. O.C. was also supported in part by the University at Buffalo Presidential Fellowship, and the National Institute of Health’s Initiative for Maximizing Student Development Training Grant T32 GM144920. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors declare no conflicts of interest with the contents of this article.
