Highly pathogenic influenza strains H5N1 and H1N1 are currently treated withinhibitors of the surface protein neuraminidase (N1). The protein includes aconserved, high affinity calcium binding site located near the active site. Thespecific role of this calcium in the enzyme mechanism is unknown, though it isshown to be important for enzyme activity and thermostability. MD simulationsof calcium-included and calcium-free complexes of N1 and the drug Tamifluindependently use both Amber and Gromos forcefields and reveal the influence ofthis calcium on N1 dynamics, particularly for stability of key binding siteresidues. Thermodynamic integration free energy calculations for thesecomplexes indicate the calcium impact of ~3 kcal mol-1 on the freeenergy of binding.  The contribution of this calcium to active site stability is particularly crucialfor structural models used in computational drug design efforts such as virtualscreening and free energy methods.

Impact of calcium on N1 influenza neuraminidase dynamics and
free energy of binding

239th National Meeting (2010)

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Impact of calcium on N1 influenza neuraminidase dynamics and free energy of binding