Free Energetics of Arginine Permeation into Model DMPC Lipid Bilayers: Coupling of Effective Counterion Concentration and Lateral Bilayer Dimensions

Abstract

Mechanisms and underlying thermodynamic determinants of translocation of charged cationic peptides such as cell-penetrating peptides across the cellular membrane continue to receive much attention. Two widely-held views include endocytotic and non-endocytotic (diffusive) processes of permeant transfer across the bilayer. Considering a purely diffusive process, we consider the free energetics of translocation of a mono-arginine peptide mimic across a model DMPC bilayer. We compute potentials of mean force for the transfer of a charged mono-arginine peptide unit from water to the center of a 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC) model lipid bilayer. We use fully atomistic molecular dynamics simulations coupled with the adaptive biasing force (ABF) method for free energy estimation. The estimated potential of mean force difference from bulk to bilayer center is 6.94 ± 0.28 kcal/mol. The order of magnitude of this prediction is consistent with past experimental estimates of arginine partitioning into physiological bilayers in the context of translocon-based experiments, though the correlation between the bench and computer experiments is not unambiguous. Moreover, the present value is roughly one-half of previous estimates based on all-atom molecular dynamics free energy calculations. We trace the differences between the present and earlier calculations to system sizes used in the simulations, and the dependence of the contributions to the free energy from various system components (water, lipids, ions, peptide) on overall system size. By varying the bilayer lateral dimensions in simulations using only sufficient numbers of counterions to maintain overall system charge neutrality, we find the possibility of an inherent convergent transfer free energy value.

Membrane Permeation of a Peptide: It Is Better to be Positive

“…Permeations of arginine amino acids or side chains were illustrated computationally and experimentally. 8, 11–12, 32–34 On the other hand arginine experiments are not necessarily a measure of charge effect on permeation. For example, it is possible that the long hydrophobic chain of arginine facilitates its permeation and not necessarily the charge, which is the focus of our discussion here.…”

Maximally asymmetric transbilayer distribution of anionic lipids alters the structure and interaction with lipids of an amyloidogenic protein dimer bound to the membrane surface

“…This is because our focus is on the interactions between lipid and proteins without the complications of salt–lipid and salt–protein interactions. As indicated in a recent review on force fields (Sun et al, 2015), there is ongoing debates and refinement of force field parameter for ion or salt interactions with lipids, particularly charged lipids (Pandit and Berkowitz, 2002; Bockmann et al, 2003; Pandit et al, 2003; Mukhopadhyay et al, 2004; Cordomi et al, 2009; Pastor and Mackerell, 2011; Hu et al, 2013; Venable et al, 2013). …”

“…All atom force fields, like CHARMM and AMBER, united atom force fields, like CHARMM—united atom, GROMOS and mixed all atom and united atom force fields are constantly developed and parameterized with experiments. At present, all atom force fields have limitations in simulating membrane potential and ion-lipid interactions involving protein, and are therefore not ready to simulate large, multiple component membrane systems containing anionic lipids, ions and protein (Cordomi et al, 2009; Pastor and Mackerell, 2011; Hu et al, 2013; Venable et al, 2013). …”

“…This is because we would like to focus on key interactions involving lipid and protein. This approach of not including salt in protein/lipid interaction simulation is well accepted in various studies using either united atom or all-atom force fields (Herce and Garcia, 2007; Dunkin et al, 2011; Hu et al, 2013; Huang and Garcia, 2013; Pourmousa and Karttunen, 2013; Park et al, 2015). …”

Predicting solute partitioning in lipid bilayers: Free energies and partition coefficients from molecular dynamics simulations and COSMOmic

“…54 However, other studies have shown that the system size can have a large influence on the result of charged solute partitioning. 55 In all simulations we used 128 lipids, resulting in a ratio of 64 lipids per solute, which should be sufficient for the uncharged solutes studied in this work. By using two solutes two free energy profiles are obtained, and an averaged profile with error bars could be calculated.…”