Interactions of Water and Alkanes: Modifying Additive Force Fields to Account for Polarization Effects

Abstract

Atomistic biomolecular simulations predominantly utilize additive force fields (FF), where the electrostatic potential is modeled by fixed point charges. Among other consequences, the lack of polarizability in these models undermines the balance of hydrophilic/hydrophobic non-bonded interactions. Simulations of water/alkane systems using the TIP3P water model and CHARMM36 parameters reveal a 1 kcal/mol overestimate of the experimental transfer free energy of water to hexadecane; more recent optimized water models (SPC/E, TIP4P/2005, TIP4P-Ew, TIP3P-FB, TIP4P-FB, OPC, TIP4P-D) overestimate this transfer free energy by approximately 2 kcal/mol. In contrast, the polarizable SWM4-NDP and SWM6 water models reproduce experimental values to within statistical error. As an alternative to explicitly modeling polarizability, this paper develops an efficient automated workflow to optimize pair-specific Lennard-Jones parameters within an additive FF. Water/hexadecane is used as a prototype and the free energy of water transfer to hexadecane as a target. The optimized model yields quantitative agreement with the experimental transfer free energy and improves the water/hexadecane interfacial tension by 6%. Simulations of five different lipid bilayers show a strong increase of water permeabilities compared to the unmodified CHARMM36 lipid FF which consistently improves match with experiment: the orderof-magnitude underestimate for monounsaturated bilayers is rectified and the factor of 2.8-4 underestimate for saturated bilayers is turned into a factor of1.5-3 overestimate. While agreement with experiment is decreased for the diffusion constant of water in hexadecane, alkane transfer free energies, and the bilayers' area per lipid, the method provides a permeant-specific

Permeability of membranes in the liquid ordered and liquid disordered phases

“…The sevenfold reduction carries a high uncertainty, and nearly includes the threefold reduction found for oxygen. It should be noted that the permeability of water in fluid-phase DOPC simulated with the same methodology 10 is approximately a factor-of-10 lower than the experiment 29 , as anticipated for a nonpolarizable force field 10,18 . Consequently, the focus of the following analysis is on the ratios and trends from simulations of different phases rather than on averages from a particular phase.…”

“…Last, their permeabilities have been extensively simulated in fluid ( L α ) phase lipid bilayers, informing the comparison with L o and L d phases. In particular, recent simulations have examined the modulation of oxygen permeability by different lipids 11–13 and cholesterol 14–16 , and have probed the effects of potential energy functions on water permeability 17,18 .…”

Breakage of Hydrophobic Contacts Limits the Rate of Passive Lipid Exchange Between Membranes

“…(2) Inaccuracies in the force field may cause errors in the calculated free energy surface. Based on reported differences between permeabilities and partition coefficients for water, alkanes, and other small molecules obtained from simulations with CHARMM36 and from experiments, 64,65 we estimate that errors due to the force field are approximately 1 − 2 k B T . We also repeated our calculations using a different force field (Stockholm lipids, also known as Slipids 66,67 ) as detailed in the SI.…”

Physical Characterization of Triolein and Implications for Its Role in Lipid Droplet Biogenesis

“…The surface tension became reduced to < 20 mN/m when using C36 or C36/LJ-PME-r, verifying the necessity of reducing the distribution of partial charges in the ester group. Although the additive force field cannot take into account polarization therefore cannot accurately produce the water density in nonpolar environment unless further modified, [76][77] it is worth nothing the large difference found in the water density at the TG layer. While C36 and C36/LJ-PME demonstrate the high water density (~10 -2 g/cm 3 ), C36/LJ-PME-r shows the low water density (~10 -3 g/cm 3 ), which agrees with the experimentally measured density (1.8 x 10 -3 g/cm 3 ).…”