Using open data to rapidly benchmark biomolecular simulations: Phospholipid conformational dynamics

Abstract

Molecular dynamics (MD) simulations are widely used to monitor time-resolved motions of biomacromolecules, although it often remains unknown how closely the conformational dynamics correspond to those occurring in real life. Here, we used a large set of open-access MD trajectories of phosphatidylcholine (PC) lipid bilayers to benchmark the conformational dynamics in several contemporary MD models (force fields) against nuclear magnetic resonance (NMR) data available in the literature: effective correlation times and spin-lattice relaxation rates.We found none of the tested MD models to fully reproduce the conformational dynamics. That said, the dynamics in CHARMM36 and Slipids are more realistic than in the Amber Lipid14, OPLS-based MacRog, and GROMOS-based Berger force fields, whose sampling of the glycerol backbone conformations is too slow. The performance of CHARMM36 persists when cholesterol is added to the bilayer, and when the hydration level is reduced. However, for conformational dynamics of the PC headgroup, both with and without cholesterol, Slipids provides the most realistic description, because CHARMM36 overestimates the relative weight of ~1-ns processes in the headgroup dynamics.We stress that not a single new simulation was run for the present work. This demonstrates the worth of open-access MD trajectory databanks for the indispensable step of any serious MD study: Benchmarking the available force fields. We believe this proof of principle will inspire other novel applications of MD trajectory databanks, and thus aid in developing biomolecular MD simulations into a true computational microscope—not only for lipid membranes, but for all biomacromolecular systems.Graphical TOC Entry

Inverse Conformational Selection in Lipid–Protein Binding

“…To experimentally characterize the differences in headgroup conformational ensembles of lipids that are not bound to proteins, we measured the C−H bond order parameters S CH and their signs for 1-palmitoyl-2-oleoylsn-glycero-3-phospho-(1′-rac-glycerol) (POPG) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) in the liquid lamellar phase, as we did previously for POPC and POPS. 32−34 Determination of headgroup and glycerol backbone S CH and their signs was straightforward from the data in 13 C NMR spectroscopy for POPE (310 K) and POPG (298 K), as measured in this work, and from data previously reported for POPS (298 K) 32 and POPC (300 K). 33,34 Empty symbols show headgroup and glycerol backbone S CH magnitudes measured previously with 2 H NMR and are also plotted as real values using the signs determined in this work for POPG with 10 mM PIPES (298 K), 35 DPPG with 10 mM PIPES and 100 mM NaCl (314 K), 20 DPPE (341 K), 36 and E. coli PE and E. coli PG with 10 mM PIPES and 100 mM NaCl (310 K).…”

“…Differences between Lipid Headgroups from 13 C NMR Experiments. To experimentally characterize the differences in headgroup conformational ensembles of lipids that are not bound to proteins, we measured the C−H bond order parameters S CH and their signs for 1-palmitoyl-2-oleoylsn-glycero-3-phospho-(1′-rac-glycerol) (POPG) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) in the liquid lamellar phase, as we did previously for POPC and POPS.…”

“…11 In the liquid bilayer state, individual phosphatidylcholine lipids sample the conformational ensemble on the nanosecond time scale. 12,13 The most accurate experimental information on conformational ensembles of lipids in this biologically relevant phase is typically derived from NMR experiments, particularly from the C−H bond order parameters, S CH = 1 / 2 ⟨3 cos 2 θ − 1⟩, where θ is the angle between the C−H bond and membrane normal, and the average is taken over the conformational ensemble of lipids. 14−16 Because these order parameters are similar to those in living cells, 17−19 experiments, the glycerol backbone conformations are largely similar, irrespective of the headgroup, 17 and the headgroup conformations are similar in the phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylglycerol (PG) lipids, whereas the phosphatidylserine (PS) headgroup is more rigid.…”

CHARMM36 Lipid Force Field with Explicit Treatment of Long-Range Dispersion: Parametrization and Validation for PE, PG, and Ether Lipids

“…At high frequency (150.84 MHz), T1 of carbon G2 is overestimated compared to the sonicated vesicle data from Brown et al 75 However, a more recent measurement 84 here, this indicates that C36/LJ-PME predicts the T1 of carbon G2 precisely. However, the same authors pointed out in another paper 85 that C36 underestimates the T1 for the β and α segments due to the high weights of motion at the 0.1-1 ns timescale. An explanation for this could be the too fast diffusion of the TIP3P water considering these segments are close to the aqueous phase, though it is hard to quantify the influence.…”

A Short Review of Current Computational Concepts for High-Pressure Phase Transition Studies in Molecular Crystals

“…Force Field methods represent the functional form and parameter sets used to calculate the potential energy of a system of atoms or coarse-grained particles in molecular mechanics and molecular dynamics simulations. They are known widely due to their implementation in molecular dynamics for different systems, including biological ones [68,69]. Much less known but still frequently used "static" FF methods can evaluate lattice energies and some properties of molecular crystals [70][71][72][73][74].…”