Computer simulations of membrane protein folding: structure and dynamics

Abstract

A lattice model of membrane proteins with a composite energy function is proposed to study their folding dynamics and native structures using Monte Carlo simulations. This model successfully predicts the seven helix bundle structure of sensory rhodopsin I by practicing a three-stage folding. Folding dynamics of a transmembrane segment into a helix is further investigated by varying the cooperativity in the formation of alpha helices for both random folding and assisted folding. The chain length dependence of the folding time of a hydrophobic segment to a helical state is studied for both free and anchored chains. An unusual length dependence in the folding time of anchored chains is observed.

FIGURE 1

One protein chain of 15 residues confined in a membrane is shown. The membrane phase separates two water phases. All residues are shown in one plane for convenience, although the simulations are done in three dimensions.

FIGURE 2

The average hydropathy index of SRI for a window of 20 amino acids. Seven transmembrane segments (TMSs) are predicted for SRI from optimizing the hydropathical interaction. The schematic representation of SRI above the hydropathy profile shows seven TMSs (filled rectangles) and eight coils (dash lines). The inset shows the hydrophobic energy reduction for various window sizes. Filled circles are results from using uniform window size ranging from 16 to 25. The filled square is a further minimization of the hydrophobic energy by varying the length of each transmembrane segment obtained from using window size 20.

FIGURE 3

A comparison of the PDB secondary structure (A) and our predictions of SRI for L = 23 (B) and L = 24 (C). Each helix is represented by a filled rectangle. Those numbers along the chain label the corresponding amino acids at both ends of transmembrane helices. The parameters used are e₁ = 0.3, e₂ = 0, e₃ = 0.3, e₄ = 1.5, P = 0.1.

FIGURE 4

A comparison of the PDB tertiary structure (A) and our prediction (B) of SRI. Seven helices are labeled according to their position along the sequence. Flexible regions of SRI are not shown in (A). The parameters used are e₁ = 0.3, e₂ = 0.3, e₃ = 0.3, e₄ = 1.5, P = 0.1.

FIGURE 5

The dependence of folding time of a transmembrane helix on cooperative factor for both random folding and assisted folding. The parameters used are e₁ = 0.3, e₂ = 0, e₃ = 0.3, e₄ = 1.5, P = 0.1, T = 0.31, and L = 24.

FIGURE 6

The dependence of the MFPT of a transmembrane helix on chain length for both free (open squares: rotating kinetics 1; filled squares: rotating kinetics 2) and anchored chains (open circles: rotating kinetics 1; filled circles: rotating kinetics 2). The parameters used are e₁ = 0.3, e₂ = 0, e₃ = 0.3, e₄ = 1.5, P = 0.1, T = 0.31, and L = 24.