Of mice and men: Dissecting the interaction between Listeria monocytogenes Internalin A and murine vs human E-Cadherin,

• We report a study of the interaction between internalin A (inlA) and human or murine E-cadherin (Ecad). inlA is used by Listeria monocytogenes to internalize itself into host cell, but the bacterium is unable to invade murine cells, which has been attributed to the difference in sequence between hEcad and mEcad. Using molecular dynamics simulations, MM/GBSA free energy calculations, hydrogen bond analysis, water characterization and umbrella sampling, we provide a complete atomistic picture of the binding between inlA and Ecad. We dissect key residues in the protein–protein interface and analyze the energetics using MM/GBSA. From this analysis it is clear that the binding of inlA–mEcad is weaker than inlA–hEcad, on par with the experimentally observed inability of inlA to bind to mEcad. However, extended MD simulations of 200 ns in length show no destabilization of the inlA–mEcad complex and the estimation of the potential of mean force (PMF) using umbrella sampling corroborates this conclusion. The binding strength computed from the PMFs show no significant difference between the two protein complexes. Hence, our study suggests that the inability of L. monocytogenes to invade murine cells cannot be explained by processes at the nanosecond to sub-microsecond time scale probed by the simulations performed here.

Ämnesord

NATURVETENSKAP  -- Kemi -- Fysikalisk kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences -- Physical Chemistry (hsv//eng)

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

NATURVETENSKAP  -- Kemi -- Teoretisk kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences -- Theoretical Chemistry (hsv//eng)

Nyckelord

Internalin A

E-cadherin

molecular dynamics

energy decomposition

umbrella sampling

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