Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane

Abstract

Bilayers of mycolic acids (MAs) form the outer membrane of Mycobacterium tuberculosis that has high strength and extremely low permeability for external molecules (including antibiotics). For the first time, we were able to study them using the all-atom long-term molecular dynamic simulations (from 300 ns up to 1.2 μs) in order to investigate the conformational changes and most favorable structures of the mycobacterial membranes. The structure and properties of the membranes are crucially dependent on the initial packing of the α-mycolic acid (AMA) molecules, as well as on the presence of the secondary membrane components, keto- and methoxy mycolic acids (KMAs and MMAs). In the case of AMA-based membranes, the most labile conformation is W while other types of conformations (sU as well as sZ, eU, and eZ) are much more stable. In the multicomponent membranes, the presence of the KMA and MMA components (in the W conformation) additionally stabilizes both the W and eU conformations of AMA. The membrane in which AMA prevails in the eU conformation is much thicker and, at the same time, much denser. Such a packing of the MA molecules promotes the formation of a significantly stronger outer mycobacterial membrane that should be much more resistant to the threatening external factors.

Biophysical Interaction Landscape of Mycobacterial Mycolic Acids and Phenolic Glycolipids with Host Macrophage Membranes

“…It has been reported that each MA possesses distinct physicochemical attributes leading to diverse lipid phases spanned by these species. MA chains adopt various conformations; , the four-chain W-shaped parallel chain configuration (highest packing efficiency), folded-extended conformation, and fully extended states (least packing efficiency). While both alpha and MeO-MA (accounting for >50% abundance) possess low packing efficiency and form liquid condensed lipid phases, keto-MA exhibits highest rigidity forming solid condensed lipid phases .…”

Molecular Modeling and Simulation of the Mycobacterial Cell Envelope: From Individual Components to Cell Envelope Assemblies

“…The latter two mycolates are composed of two subclasses having either cis -cyclopropane rings or trans -cyclopropane rings with an adjacent methyl branch. The fact that cyclopropanation of fatty acids may provide both stabilization and fluidity of bacterial membranes against adverse conditions has been shown using all-atom and coarse-grained MD simulations. , The MA classes occur naturally with variations in the numbers of carbons ranging from 60 to 90 for Mtb , and they appear to be predominately located in the inner leaflet of the MOM. , Recent physiochemical investigations indicate that MAs adopt different folded conformations from a compact “W” conformation, similar to four parallel chains, to more extended conformations such as semifolded “sZ” and extended “eU” conformations. − These different folding patterns were explored some time ago using all-atom MD simulations, , while both coarse-grained and all-atom modeling was more recently used to investigate the assembly of MAs in monolayers and bilayers. , Trehalose dimycolate (TDM) and trehalose monomycolate (TMM), the so-called “cord factors”, are the best known MA esters in mycobacteria. , TDM is formed by a polar headgroup of trehalose (Glcα1↔1αGlc) and by two mycolates esterified to O6 of the hydroxymethyl group of each glucose molecule. To the best of our knowledge, there are currently no MD simulation studies of membranes constituted by large TMM or TDM molecules, although we are aware of the modeling of a symmetrical bilayer constituted by short TDM molecules from corynebacteria .…”

“… 30 − 32 These different folding patterns were explored some time ago using all-atom MD simulations, 33 , 34 while both coarse-grained and all-atom modeling was more recently used to investigate the assembly of MAs in monolayers and bilayers. 35 , 36 Trehalose dimycolate (TDM) and trehalose monomycolate (TMM), the so-called “cord factors”, are the best known MA esters in mycobacteria. 25 , 37 TDM is formed by a polar headgroup of trehalose (Glcα1↔1αGlc) and by two mycolates esterified to O6 of the hydroxymethyl group of each glucose molecule.…”

Emerging Extracellular Molecular Targets for Innovative Pharmacological Approaches to Resistant Mtb Infection

“…The conformation of the MA plays an important role in the resistance and strength of the Mtb cell wall [ 12 , 13 ]. Recent studies on the conformation of the MA layer identified that the so-called U conformation, with a single bend, is the most stable, while the W conformation, with two bends, is more labile [ 14 ]. It is suggested that the majority of MA are in U single-bend conformation, resulting in substantially thicker and denser membranes.…”