Macromolecular Modeling Blog ™

I’m happy to cross-post another elegant piece written by the MD specialist Bosco Ho. In this post Bosco compares the performance of Molecular Dynamics simulations with Monte Carlo simulations in reconstructing NMR S order parameters for microsecond biological processes. Curious to know which is better ?

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Although numerous structures of peptide bound MHC-II molecules were solved, no one knows how does the peptide free MHC look like. Painter et al. elegantly use molecular dynamics to model the conformational changes upon peptide removal. Most interestingly a helix from the peptide binding domain adopts the binding mode of the antigen peptide. They successfully validate their model using antibodies and superantigens, predicted to differentially bind peptide-bound/free molecules according to their model. We take the validation one step further and propose mutations based on Painter’s model that would stabilize the free MHC. Will it work? Who will pick up the gauntlet?

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Carlos J. Camacho et al. study the relationship between peptide stabilities and their immunogenicity. They present a model system of several peptides corresponding to portions of murine HRS which are capable of inducing anti-protein antibodies of varying affinity and temporal persistence. On this system they show by molecular dynamics simulations, that sequences of the most immunogenic peptides correspond to highly ordered structural motifs in the parent protein. Competitive ELISAs provide direct evidence that these peptides share structural determinants with native protein. More interestingly they address the question of how can these less stable peptides induce the same immunogenic response. By Nir London

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S. Gordo et al. implement a new strategy for preventative anti-cancer therapeutics. R337H is the most frequent inherited mutation in p53, “The guardian of the genome”, and is associated with wide spectrum of cancer forms. The mutation is believed to destabilize the native tetramer form of p53. In this study the researchers designed a small molecule that reconstitutes tetramerization of such a mutant. By Nir London.

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Incorporation of flexibility into docking simulations and accounting for backbone conformational changes during association is probably the toughest problem protein-protein dockers are facing today. Normal Mode Analysis is lately the answer of many groups to this problem. We hereby review two approaches of incorporating NMA into docking simulations, reflecting the induced fit vs. conformational sampling association mechanisms. 

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