COGRIMEN: Coarse-Grained Method for Modeling of Membrane Proteins in Implicit Environments

Abstract

The presented methodology is based on coarse-grained representation of biomolecules in implicit environments and is designed for the molecular dynamics simulations of membrane proteins and their complexes. The membrane proteins are not only found in the cell membrane but also in all membranous compartments of the cell: Golgi apparatus, mitochondria, endosomes and lysosomes, and they usually form large complexes. To investigate such systems the methodology is proposed based on two independent approaches combining the coarse-grained MARTINI model for proteins and the effective energy function to mimic the water/membrane environments. The latter is based on the implicit environment developed for all-atom simulations in the IMM1 method. The force field solvation parameters for COGRIMEN were initially calculated from IMM1 all-atom parameters and then optimized using Genetic Algorithms. The new methodology was tested on membrane proteins, their complexes and oligomers. COGRIMEN method is implemented as a patch for NAMD program and can be useful for fast and brief studies of large membrane protein complexes.

Figure 1

Coarse-grained mapping of amino acids according to MARTINI force field (color denotes properties of grains: purple, apolar; blue and green, intermediate; gray and orange, polar; red, charged). Figure based on Figure 3 from ref (50).

Figure 2

An implicit solvent method IMM1. (A) A continuous change of solvation potential in a water-membrane system. (B) A rhodopsin molecule simulated in the implicit membrane environment. Pink surfaces denote pure hydrophobic part of the membrane, blue surfaces denote bulk water areas, while the space between them corresponds to the transition area. Reproduced from Reference (1) by permission from Springer Nature Customer Service Centre GmbH: Latek, D.; Trzaskowski, B.; Niewieczerzal, S.; Miszta, P.; Mlynarczyk, K.; Debinski, A.; Pulawski, W.; Yuan, S.; Sztyler, A.; Orzel, U.; Jakowiecki, J.; Filipek, S. Modeling of Membrane Proteins. In Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes; Liwo, A., Ed.; 2019; Vol. 8, pp 371–451. Copyright 2014, Springer Nature.

Figure 3

Training set of proteins taken for development of solvation parameters with their PDB IDs. (A) barstar protein; (B) bacterial chemotaxis protein CheY; (C) 4TM isolated voltage-sensing domain; (D) 7TM CB1 cannabinoid receptor; (E) the outer membrane protein OmpX; (F) the outer membrane protein OmpA; (G) trimer of bacteriorhodopsin from Halobacterium salinarum; (H) trimer of maltoporin from Escherichia coli; (I) a trimer composed of membranous β-barrel and the extramembrane helical bundle of anchor protein from Yersinia enterocolitica. Colors in panels A–F denote the secondary elements in particular proteins. Colors in panels G–I denote particular monomers. For membrane proteins the membrane is marked by red and blue dotted surfaces. The membrane thicknesses for individual proteins and complexes were taken from Orientations of Proteins in Membranes (OPM) database.

Figure 4

Crystal structures of GPCR complexes with effector proteins. (A) A complex of β2-adrenergic receptor with Gs trimer (G_αβγ) (PDB id: 3SN6). (B) A complex of rhodopsin with arrestin (PDB id: 4ZWJ). In both panels the receptor is colored in green while the contact between receptor and the effector protein is marked by a semitransparent orange rectangle.

Figure 5

Structures and statistics from 10 μs MD CG simulation of complex of β2-adrenergic receptor with Gs trimer (G_αβγ) (PDB id: 3SN6). Top-left: superimposition of CG structures, initial (green for receptor, red for G_α, blue for G_β, and yellow for G_γ) and final (cyan for receptor, purple for G_α, gray for G_β, and orange for G_γ). Top-right: histograms of 1–4 distance and 1–4 dihedral angle of α-helical and β-sheet parts of the complex during entire simulation. Bottom: RMSD and radius of gyration plots for receptor, and for trimeric G protein. Dashed vertical lines in histogram plots indicate the reference values for distances and dihedral angles.

Figure 6

Structures and statistics from 10 μs MD CG simulation of human rhodopsin bound to arrestin (PDB id: 4ZWJ). Top-left: superimposition of CG structures, initial (green for receptor and red for arrestin) and final (cyan for receptor and purple for arrestin). Top-right: histograms of 1–4 distance and 1–4 dihedral angle of α-helical and β-sheet parts of the complex during entire simulation. Bottom: RMSD and radius of gyration plots for receptor and for arrestin. Dashed vertical lines in histogram plots indicate the reference values for distances and dihedral angles.