Dynamics of Lipids, Cholesterol, and Transmembrane α-Helices from Microsecond Molecular Dynamics Simulations

Abstract

Extensive all-atom molecular dynamics (∼24 μs total) allowed exploration of configurational space and calculation of lateral diffusion coefficients of the components of a protein-embedded, cholesterol-containing model bilayer. The three model membranes are composed of an ∼50/50 (by mole) dipalmitoylphosphatidylcholine (DPPC)/cholesterol bilayer and contained an α-helical transmembrane protein (HIV-1 gp41 TM). Despite the high concentration of cholesterol, normal Brownian motion was observed and the calculated diffusion coefficients (on the order of 10–9 cm2/s) are consistent with experiments. Diffusion is sensitive to a variety of parameters, and a temperature difference of ∼4 K from thermostat artifacts resulted in 2–10-fold differences in diffusion coefficients and significant differences in lipid order, membrane thickness, and unit cell area. Also, the specific peptide sequence likely underlies the consistently observed faster diffusion in one leaflet. Although the simulations here present molecular dynamics (MD) an order of magnitude longer than those from previous studies, the three systems did not approach ergodicity. The distributions of cholesterol and DPPC around the peptides changed on the microsecond time scale, but not significantly enough to thoroughly explore configurational space. These simulations support conclusions of other recent microsecond MD in that even longer time scales are needed for equilibration of model membranes and simulations of more realistic cellular or viral bilayers.

HIV-1 Env gp41 Transmembrane Domain Dynamics Are Modulated by Lipid, Water, and Ion Interactions

“…All-atom molecular dynamics (MD) simulations offer a robust approach to reveal the dynamics of the TMD and its effect on membrane biophysical properties. However, previous MD simulations of the TMD were limited by the structural information that was available at the time of simulation, including factors such as the initial protein conformation, membrane composition, oligomeric state, R696 protonation state, and simulation duration (27)(28)(29)(30). Prior TMD MD models were either derived by homology modeling using the HIV transmembrane viral protein U as a template (27)(28)(29) or from a 20-amino-acid transmembrane de novo model (30) rather than the recently published trimeric NMR TMD structure (20) that was used in this study.…”

HIV-1 Env gp41 Transmembrane Domain Dynamics are Modulated by Lipid, Water, and Ion Interactions

“…All-atom molecular dynamics (MD) simulations offer a robust approach to reveal the dynamics of the TMD and its effect on membrane biophysical properties. However, previous MD simulations of the TMD were limited by the structural information that was available at the time of simulation, including factors such as the initial protein conformation, membrane composition, oligomeric state, R696 protonation state, and simulation duration (28)(29)(30)(31). Prior TMD MD models were either derived by homology modeling using the HIV transmembrane viral protein U (Vpu) as template (28)(29)(30) or from a 20amino acid transmembrane de novo model (31) rather than the recently published trimeric NMR TMD structure (21) which was used in this study.…”

“…However, previous MD simulations of the TMD were limited by the structural information that was available at the time of simulation, including factors such as the initial protein conformation, membrane composition, oligomeric state, R696 protonation state, and simulation duration (28)(29)(30)(31). Prior TMD MD models were either derived by homology modeling using the HIV transmembrane viral protein U (Vpu) as template (28)(29)(30) or from a 20amino acid transmembrane de novo model (31) rather than the recently published trimeric NMR TMD structure (21) which was used in this study. Previous simulations that used monomeric transmembrane models (28)(29)(30) lack quaternary contacts that are believed to stabilize the internal arginine (R696) (21,24,25).…”

“…Prior TMD MD models were either derived by homology modeling using the HIV transmembrane viral protein U (Vpu) as template (28)(29)(30) or from a 20amino acid transmembrane de novo model (31) rather than the recently published trimeric NMR TMD structure (21) which was used in this study. Previous simulations that used monomeric transmembrane models (28)(29)(30) lack quaternary contacts that are believed to stabilize the internal arginine (R696) (21,24,25). Furthermore, previous MD simulations were limited in sampling and membrane composition and were therefore unable to reveal the complex properties of the membrane components and their effect on TMD dynamics (28)(29)(30)(31).…”

“…Previous simulations that used monomeric transmembrane models (28)(29)(30) lack quaternary contacts that are believed to stabilize the internal arginine (R696) (21,24,25). Furthermore, previous MD simulations were limited in sampling and membrane composition and were therefore unable to reveal the complex properties of the membrane components and their effect on TMD dynamics (28)(29)(30)(31). More recently, discussion has formed around the ability of the TMD to exist in reconstituted bicelles as a monomer (23) and the potential role of key arginine residues in stabilizing either a monomeric or a trimeric transmembrane structure (24).…”