Interactions of amino acid side-chain analogs within membrane environments

Abstract

The interactions among four amino acid analog pairs (Asn, Ser, Phe, and Val) within the membrane environment were investigated using umbrella sampling molecular dynamics simulations. The results confirm generally expected qualitative trends of preferential association of polar compounds inside the membrane vs preferential interaction of hydrophobic compounds outside the membrane. Furthermore, correlations between amino acid interactions, membrane insertion, and membrane deformations are discussed and a detailed analysis of pair interaction energies is presented. A comparison of the energetics obtained from explicit lipid simulations with those from implicit membrane models reveals significant deviations and an improved parametrization of the heterogeneous dielectric generalized Born implicit model is provided that partially corrects for deficiencies in the implicit membrane model when compared with the new reference data from this study.

Figure 1

Local membrane thickness of the upper leaflet as a function of the radial distance from the center of the amino acid analog pairs at different distances from the center of the membrane. A: sampling in forward direction; B: sampling in backward direction. Local thickness is calculated as average z of phosphorous atoms in the upper leaflet which fall into radial slabs of width 4 Å.

Figure 2

Potentials of mean force as a function of water density to reflect membrane deformation. A: acetamide pair at z=0 and d=5.5 Å; B: methanol pair at z=0 and d=4.5 Å.

Figure 3

Potential of mean force for acetamide as a function of pair distance at different insertion depth into the lipid bilayer from simulations with A) explicit solvent and lipids B) HDGB implicit membrane C) GBSW implicit membrane and D) IMM1 implicit membrane models; For each insertion depth, the bound state was used as the reference with an energy of zero. The white bars indicate a lack of sampling overlap along the z direction.

Figure 4

PMF of methanol as in Fig. 3.

Figure 5

PMF of toluene as in Fig. 3.

Figure 6

PMF of propane as in Fig. 3.

Figure 7

Conformational analysis of acetamide pair at the bound state; A) average hydrogen bonds formed between acetamide pair and water molecules as a function of bilayer normal distance, B) fraction of conformations that form one intra-pair hydrogen bond, C) fraction of conformations forming two intra-pair hydrogen bonds; The results of explicit (blue), HDGB (red), GBSW (green), and IMM1 (purple) are compared.

Figure 8

Two representative bound conformation for methanol pair resulting in a different binding distance.

Figure 9

PMF profiles for acetamide, methanol, toluene, and propane at Z=0 and Z=12 as a function of the pair distance obtained from explicit, HDGB, GBSW, and EEF1 models