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. 2018 Sep 15;10(5):1371–1376. doi: 10.1007/s12551-018-0454-z

The effect of H3O+ on the membrane morphology and hydrogen bonding of a phospholipid bilayer

Evelyne Deplazes 1, David Poger 2, Bruce Cornell 3, Charles G Cranfield 4,✉
PMCID: PMC6233341  PMID: 30219992

Abstract

At the 2017 meeting of the Australian Society for Biophysics, we presented the combined results from two recent studies showing how hydronium ions (H3O+) modulate the structure and ion permeability of phospholipid bilayers. In the first study, the impact of H3O+ on lipid packing had been identified using tethered bilayer lipid membranes in conjunction with electrical impedance spectroscopy and neutron reflectometry. The increased presence of H3O+ (i.e. lower pH) led to a significant reduction in membrane conductivity and increased membrane thickness. A first-order explanation for the effect was assigned to alterations in the steric packing of the membrane lipids. Changes in packing were described by a critical packing parameter (CPP) related to the interfacial area and volume and shape of the membrane lipids. We proposed that increasing the concentraton of H3O+ resulted in stronger hydrogen bonding between the phosphate oxygens at the water–lipid interface leading to a reduced area per lipid and slightly increased membrane thickness. At the meeting, a molecular model for these pH effects based on the result of our second study was presented. Multiple μs-long, unrestrained molecular dynamic (MD) simulations of a phosphatidylcholine lipid bilayer were carried out and showed a concentration dependent reduction in the area per lipid and an increase in bilayer thickness, in agreement with experimental data. Further, H3O+ preferentially accumulated at the water–lipid interface, suggesting the localised pH at the membrane surface is much lower than the bulk bathing solution. Another significant finding was that the hydrogen bonds formed by H3O+ ions with lipid headgroup oxygens are, on average, shorter in length and longer-lived than the ones formed in bulk water. In addition, the H3O+ ions resided for longer periods in association with the carbonyl oxygens than with either phosphate oxygen in lipids. In summary, the MD simulations support a model where the hydrogen bonding capacity of H3O+ for carbonyl and phosphate oxygens is the origin of the pH-induced changes in lipid packing in phospholipid membranes. These molecular-level studies are an important step towards a better understanding of the effect of pH on biological membranes.

Keywords: H3O+, Phospholipid bilayers, Hydrogen bonding, Critical packing parameter, Molecular dynamics simulations

Introduction

How lipid bilayers respond to various external factors such as temperature (Basu et al. 2001; Blicher et al. 2009; Veatch and Keller 2005), pressure (Chen et al. 2011; Winter 2001) and salt concentrations (Aroti et al. 2007; Berkowitz and Vácha 2012; Petrache et al. 2006; Song et al. 2014) has been studied extensively over the past decades. In contrast, the effect of pH on the structure of lipid bilayers has been less examined leading to a poor understanding of this effect at a molecular level. Yet pH-induced changes in membranes play a critical role in many biological processes including the stability and integrity of the lysosomal membranes (Carreira et al. 2017), the formation of cholesterol-enriched domains (Redfern and Gericke 2005) and drug partitioning (Krämer et al. 1998; Schaper et al. 2001). Our understanding of pH on biological membranes is also important to comprehending systemic health issues such as inflammation (Kellum et al. 2004), tumour growth (Gerweck and Seetharaman 1996; Kato et al. 2013), ischaemic stroke (Huang and McNamara 2004) and epileptic seizures (Ziemann et al. 2008). pH also plays an important role in understanding how some organisms have adapted to living in extreme pH environments (de Rosa et al. 1983), in the design of acidophilic bacteria for bio-mining and other biotechnology applications (Khaleque et al. 2017).

Our previous work explored the effect of the hydronium ion (H3O+) on the lipid packing (Cranfield et al. 2016) in phospholipid bilayers. This work was based on a model proposed by Jacob Israelachvili and colleagues who devised the concept of geometrical constraints that govern the phase behaviour of lipid bilayers and micelles according to a semi-predictive measure called the critical packing parameter (CPP) (Israelachvili et al. 1976). In essence, the geometry of an individual lipid can be described in terms of its volume (v), hydrocarbon–water interfacial area (a0) and chain length (l). When surfactants assemble into a supramolecular phase structure, this geometry dictates that the lipids form a bilayer structure when va0l = 1 and a micelle structure when va0l = 1/3 (Fig. 1).

Fig. 1.

Fig. 1

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The ratio between the lipid volume (v), and the hydrocarbon–water interfacial area (a0) and lipid tail length (l) describes the critical packing parameter (CPP) that dictates the collective properties in the lipid bilayer

Instead of individual lipids, if the CPP is considered for a lipid bilayer as a whole, then a model can be presented that describes changes in membrane geometry as a result of a weighted CPP (CPPw) (Cranfield et al. 2017). In order for a bilayer structure to be maintained, any changes in the phospholipid headgroup area of the lipids, a0, can be expected to have an effect on the lipid chain length, l, in order that the CPPw maintains a value close to 1. Factors that alter the bridging water molecules between phospholipid headgroups are likely to alter a0. Pearson and Pascher first identified water bridging between phospholipid headgroups via hydrogen bonding in 1979 (Pearson and Pascher 1979). If, instead, there is a greater dissociation of the water molecules such that the local hydronium ion (H3O+) concentration is increased (i.e. the pH is lower), there will be a strengthening of the fleeting hydrogen bonds between the phospholipid phosphates and/or carbonyl groups (Fig. 2) and the overall value for a0 will decrease. In order for a bilayer structure to be maintained (CPPw ~ 1), the lipid tails’ lengths (l) would need to extend.

Fig. 2.

Fig. 2

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By altering the pH, the strength and number of bridging hydrogen bonds between adjacent lipid headgroups will alter the interfacial surface area of the lipid head groups (a0). The extension of the lipid tails will change as a result (l)

Using tethered bilayer lipid membrane technology in association with electrical impedance spectroscopy and neutron reflectometry, we were able to demonstrate that there is a change in lipid packing as a result of an increase in the concentration of H3O+ and that the membrane thickness did increase marginally, consistent with the change predicted by the CPP model (Cranfield et al. 2016). It was suggested that the variations of water penetration into the bilayer and membrane conductivity observed at low pH were caused by H3O+ ions competing with and disrupting water-bridged intermolecular hydrogen bonds between lipid molecules. It was also hypothesised that the observed decrease in area per lipid was due to an enhanced stability of hydrogen bonds of H3O+ with the phosphate oxygen groups (OP1 and OP2, Fig. 3) and carbonyl oxygens (O1A and O2A) of the sn-1 and sn-2 lipid side chains.

Fig. 3.

Fig. 3

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Structure of a phospholipid molecule (2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine, POPC) showing the hydrogen bonding sites on the carbonyl and phosphate oxygens

To test these hypotheses, we carried out multiple 1-μs-long, unrestrained molecular dynamic (MD) simulations of a fully hydrated POPC (2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine) lipid bilayer in the presence of H3O+ ions equivalent to 0.04 M and 0.4 M [H3O+] (three 1-μs simulations of POPC with 0.04 M [H3O+] and 0.4 M [H3O+] each) (Deplazes et al. 2018). At these concentrations, the bulk-phase pH would be equivalent to approximately 1.4 and 0.4, respectively, and thus significantly lower than the pH values used for experiments reported in Cranfield et al., which were carried out at pH 5 (Cranfield et al. 2016). However, a number of experimental and computational studies have suggested that the local concentration of H3O+ ions at the water–lipid interface is significantly higher than that in the bulk water phase (Brändén et al. 2006; Gopta et al. 1999; Heberle et al. 1994; Slevin and Unwin 2000; Mashaghi et al. 2013; Smondyrev and Voth 2002; Wolf et al. 2014; Yamashita and Voth 2010) resulting in differences of up to four pH units.

Simulations were performed using GROMACS version 4.6.7 (Hess et al. 2008), in conjunction with the GROMOS 54A7 force field (Schmid et al. 2011) and parameters for POPC developed by Poger et al. (Poger et al. 2010; Poger and Mark 2009). The hydronium ion was modelled with the excess proton localised on a single water molecule forming a hydronium cation and a geometry similar to that used in previous studies (Bonthuis et al. 2016; Chialvo et al. 2000; Dang 2003; Gertner and Hynes 1998; Kusaka et al. 1998; Urata et al. 2005; Vácha et al. 2007). As a reference, a POPC bilayer simulated in the absence of H3O+ ions from previous studies was used (Poger and Mark 2012; Poger et al. 2010).

Key findings

Hydronium ions are attracted to the water–phospholipid interface

The hypothesis that the pH at the water–phospholipid interface is far lower than the bulk solution was supported by the simulations. At the start of the simulations, the H3O+ ions are randomly distributed in the bulk solution. Within the first 100–150 ns of the simulation, the H3O+ migrate to the water–lipid interface. The density profiles obtained from the last 500 ns of the equilibrated systems showed that the H3O+ ions accumulate around the phosphate and carbonyl groups of the phospholipids, as illustrated in Fig. 4. This uneven distribution of H3O+ ions between the water–lipid interface and bulk water means it is not trivial to estimate the ‘actual’ pH in the bathing solution of a membrane. This is further complicated by the existence of layers of ‘interfacial water’ that extend from the lipid headgroup to approximately 1 to 2 nm into bulk water (see reviews by Berkowitz and Vácha 2012; Milhaud 2003; Disalvo 2015 and references therein). Thus, not only is there an uneven distribution of H3O+ ions but the definition of where water can be treated as bulk is hard to define. Analysis of our simulations with 0.4 M [H3O+] suggests that based on the average number of H3O+ ions in bulk (defined as at least 1 nm away from the water–lipid interface), the bulk pH is approximately 2–3 pH units lower than when calculated assuming an even distribution of H3O+ ions in the system.

Fig. 4.

Fig. 4

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Snapshots from simulations of POPC with 0.4 M [H3O+] illustrating the accumulation of H3O+ ions at the water–lipid interface

Hydronium ions reduce the area per lipid and increase lipid tail length

Supporting the data obtained using tethered lipid bilayer membrane technology and neutron diffraction experiments reported previously (Cranfield et al. 2016), the addition of hydronium ions at the interface leads to a reduction in the area per lipid (Fig. 5a) as a result of hydrogen bonding. This is due to the stronger electrostatic interactions of hydroniums compared to water molecules. The CPP model suggests that a reduction in the area per lipid should be accompanied by an increase in the lipid chain length in order to maintain a bilayer structure whereby the CPPw ~ 1. The MD simulations support this CPP model with the overall membrane thickness increasing due to the presence of the hydronium ions (Fig. 5b).

Fig. 5.

Fig. 5

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Area per lipid (AL) and membrane thickness (d) as a function of time from simulations of neutral POPC (grey, brown) and in the presence of 0.04 M [H3O+] (blue, magenta, indigo) and 0.4 M [H3O+] (black, light green, dark green), in agreement with the CPP model and neutron diffraction experiments (Cranfield et al. 2016). Figure reproduced from Deplazes et al. (2018). “The effect of hydronium ions on the structure of phospholipid membranes.” Physical Chemistry Chemical Physics 20(1): 357–366. Published by the PCCP owner societies

Hydronium ions form strong hydrogen bonds with carbonyl and phosphate lipid oxygens

As illustrated in Fig. 3, POPC has several hydrogen-bonding sites through which it can interact with H3O+. Hydrogen bond analysis from simulations with 0.04 M [H3O+] and 0.4 M [H3O+] showed that the H3O+ ion preferentially interacts with the carbonyl oxygen in the sn-2 chain (O2A), followed by the non-ester phosphate oxygens OP2 and OP1 (Fig. 6a). Furthermore, an analysis of the packing of lipids around the H3O+ ions showed that for the majority of hydrogen bond bridging events, the H3O+ ion is surrounded by two or three lipid molecules. In the most populated arrangement, a H3O+ ion forms hydrogen bonds with the sn-2 carbonyl oxygens (O2A) from two lipids and the non-ester oxygen (OP1) from a third lipid (Fig. 6b). Furthermore, comparison of the distance distributions of the lipid–H3O+ and lipid–water hydrogen bonds showed that the bonds with H3O+ ion are shorter. In addition, estimates of the hydrogen bond lifetimes showed that the lipid–H3O+ bonds are significantly longer-lived than the lipid–water ones.

Fig. 6.

Fig. 6

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Hydrogen bonding of H3O+ ions. a Histograms of H bonds per H3O+ ions for the different lipid oxygens calculated from simulations of a POPC lipid bilayer in the presence of 0.04 M [H3O+] and 0.4 M [H3O+]. For each oxygen, the number of H bonds was averaged over the last 200 ns of the simulation from the three independent trajectories. b The most common hydrogen bonding networks formed by H3O+ ions and POPC lipids observed in simulations of a POPC lipid bilayer in the presence of 0.04 M [H3O+] and 0.4 M [H3O+] where a H3O+ ion forms hydrogen bonds with two sn-2 carbonyl oxygens (O2A) and one non-ester oxygen (OP1) from three different lipids molecules. Probability distribution of donor–acceptor distances distance for the hydrogen bonds formed by the lipid oxygens O2A and OP1 with the H3O+ ion and water calculated from the last 500 ns of simulations of POPC in the presence of 0.4 M [H3O+]

There are a number of computational and experimental studies that have demonstrated that the structure and dynamics of water at the interface of phospholipid bilayers (and other confined interfaces) deviates from bulk properties (see reviews by Berkowitz and Vácha 2012; Milhaud 2003; Disalvo 2015 and references therein). In addition, our recent work on the analysis of interfacial water suggests that this layer grows thicker in the presence of H3O+ ions (Deplazes et al. 2018, unpublished). Furthermore, not unexpected, the orientation of the water dipoles at the membrane surface is also affected by the H3O+ ions.

Significance

The combined data from the experiments in Cranfield et al. (2016) and Deplazes et al. (2018) provide a molecular-level picture of how the hydrogen bonding network formed by the hydronium ion and surrounding lipids changes the structure of phospholipid membranes. This work also supports the hypothesis that the H3O+ concentration at the lipid–water interface is orders of magnitude lower than that of the bulk electrolyte aqueous solution thus suggesting that the interfacial and bulk pH differ significantly. These findings highlight the significance of the phosphate and carbonyl groups within phospholipids and the mechanisms underlying the sensitivity to hydronium ion concentration in biology. The work also emphasises the importance of understanding the dynamics of water and H3O+ ions at the membrane interface (Gennis 2016; Zhang et al. 2011) and the effect of pH in biological processes in general (Lagadic-Gossman et al. 2004; Krulwich et al. 2011).

Conflict of interest

Evelyne Deplazes declares that she has no conflict of interest. David Poger declares that he has no conflict of interest. Bruce Cornell declares that he has no conflict of interest. Charles G Cranfield declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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