In mycobacterium tuberculosis, the pathogen responsible for tuberculosis (TB), pathogenicity is mediated through interactions with the host membrane, primarily by a cell-surface-associated glycolipid, lipoarabinomannan (LAM). The mannose molecule that caps LAM is a key virulence factor, and the recognition defined by mannose-membrane interactions has been implicated in the initiation of TB pathogenesis. Therefore, we seek a thorough understanding of the nature of the interactions between carbohydrates and phospholipids to dissect their roles in molecular recognition. A hybrid quantum mechanics/quantum mechanics (QM/QM) scheme with two different levels of treatment was used to explore the conformations and energetics of mannose-phospholipid complexes. Then, we have considered a combination of conventional molecular dynamics (MD) simulations, umbrella enhance sampling method and analytical models to understand the thermodynamics and kinetics of a di-mannose molecule in a phospholipid bilayer system. We observe that di-mannose has a slight preference to be located at the water-phospholipid interface. Using umbrella-sampling method, we obtain the potential of mean force that shows a slight energy bias for di-mannose to be located at the water-phospholipid interface.  With a two-phase model, we accurately calculate the absolute entropy change of water molecules when di-mannose binds to membrane. These analyses indicate that the small free energy bias is the result of favorable entropy change of water. Finally, we incorporate results from MD simulation in two different ways to an analytical model to get the association and dissociation constants for di-mannose interaction with membrane.

Recognition of sugar at membrane-water interface

244th National Meeting (2012)

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