Partial interdigitation of lipid bilayers

Abstract

A methodology has been developed to detect partial interdigitation of lipid bilayers when a bioactive molecule is intercalated between the polar, interface, or hydrophobic segments. This methodology uses the easily accessible differential scanning calorimetry (DSC) technique as a screening one and the increase of DH due to the incorporated drug in lipid bilayers as a diagnostic thermodynamic parameter. The combined use of X-ray diffraction and Raman spectroscopy complement and confirm the provided by DSC information as it is shown in three classes of molecules, namely AT 1 antagonists, vinca alkaloids, and anesthetic steroids. For the two classes of molecules, AT 1 antagonists and vinca alkaloids, their presence in lipid bilayers results in the increase of DH and it is accompanied by the increase of trans:gauche ratio and the decrease of d-spacing as depicted by Raman spectroscopy and small-angle X-ray diffraction correspondingly, confirming the predictive ability of DSC experiments. When an anesthetic steroid is incorporated in lipid bilayers, neither increase of DH nor decrease of d-spacing was observed, confirming again the DSC results that show the absence of partial interdigitation of this class of molecules. Molecular dynamics simulations have been carried out for a representative system [(5S)-1-benzylo-5-(1H-benzimidazol-1-ylo-methylo)-2-pyrrolidinone (MMK3) ligands at 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayer], and the results confirmed the experimental findings. The change of distance at z-axis of oxygen atoms at head group of lipid molecule has been measured throughout the simulations. Statistical analysis has shown $8.8 Å interdigitation. Derived computational results are encouraging and can be performed to another ligand/lipid system. The development of a theoretical methodology will lead to advance the field and save a valuable time and effort.

Structural characterization of phosphatidylglycerol model membranes containing the antibiotic target lipid II molecule: a Raman microspectroscopy study

“…The spectral behavior of the C―H stretching bands suggests that LII is unable of reaching the deep core of the DPPG membrane; in its instead partial interdigitation in the lipid bilayer is induced, as is derived from the reduced freedom of the terminal CH 3 groups of the acyl chains. The tendency of some amphiphilic, bulky membrane‐active compounds to induce hydrocarbon chain interdigitation has been well demonstrated; these biomolecules, by acting preferentially near the lipid polar interface, affect the balance between the headgroup and chain interactions and form the interdigitated phase . The limited penetration of LII into the DPPG membrane may modify the lateral stress profile at the water/bilayer interfacial region and induced partial interdigitation.…”

“…This spectral analysis is in concordance with that derived from the evaluation of the corresponding C―H stretching modes and confirms the assumption that LII induces partial interdigitation when interacts with a membrane in the gel state. The superficial penetration of LII tail into the hydrocarbon chains may alter the lateral stress at the interfacial region and causes this effect …”

“…[26][27][28][29][30][31][32][33][34] In this paper, we study the interaction of LII with phospholipid multilayer vesicles in different lipid phases by using RMS. Taking into account that (1) the negatively charged phosphatidylglycerol (PG) lipids represent the most abundant components of bacterial membranes; [35] (2) although the liquidcrystalline (L α ) phase is the biologically most relevant membrane state, biophysical studies have shown that gel (L β ′) phase plays an important role in bacterial membranes when interacts with antimicrobial peptides; [36,37] and (3) the induction of interdigitated phases in PG membranes is of high relevance to interaction studies with antimicrobial peptides because it provides a mechanism for the discrimination of membranes composed of different lipids species, [36][37][38][39] we identified and characterized structural alterations in dilauroylphosphatidylglycerol (DLPG) and dipalmitoylphosphatidylglycerol (DPPG) membrane models induced by the presence of low concentrations of LII.…”

The Quantum Casimir Effect May Be a Universal Force Organizing the Bilayer Structure of the Cell Membrane

“…Steric interactions seem to be the dominant suppressor of interdigitation. However, a spontaneous or induced interdigitated phase of bilayers consisting of double-tail lipids was confirmed in computer simulation and differential scanning calorimetry experiments (Kranenburg 2004; Kranenburg et al 2004; Mavromoustakos et al 2011). Moreover, a simple estimation below shows that the possible steric effect is not energetically dominant, as one may expect.…”

AT1 antagonists: a patent review (2008 – 2012)

“…If this molecular basis of action for AT1 antagonists is applicable, then the lipid part of membrane bilayers is an essential component in their drug action. As a matter of fact, the action of AT1 antagonists on phospholipids that constitute lipid bilayers is well documented [65][66][67][68][69][70][71][72][73][74], but there is no practical application of the experimental results in the literature. Lipidomics is a new era of drug research and this field must be developed for AT1 antagonists.…”