Macromolecular Modeling Blog ™

To all of our readers, modelers and structural biologists out there, 

May you have a happy new year, may your runs converge, may your energy find a minimum, may the protein crystalize, may predictions succeed, may your signals be strong. 

On behalf of the “Macromolecular Modeling Blog” and the “Rosetta Design Group”.

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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Instead of our regular Bi-weekly digest, Lets take a pause and dissect the trends in computational structural biology. As you may noticed, we added to the sidebar a “Structural Bioinformatics” titles feed. This feed is maintained by ~ 30 people at CiteULike, grouped by their liking to: “topics ranging from sequence-structure relationships to molecular simulations of biomolecules”. We used wordle to present popular items on that feed (around 1350 titles) and the results are striking.

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G-protein coupled receptors comprise a large family of receptors that mediates signal transduction pathways. This family is extremely important and is the hub of drug discovery efforts. A recent market research reports that GPCR targeted drugs which now account for 25% of the pharmaceutical market are expected to increase market share to nearly 50% by 2012. While major pharma companies are increasingly entering into collaborations with GPCR platform development companies leading to pathbreaking drug discoveries. From the structural biology point of view it was just recently that a second crystal structure of a GPCR was solved, meaning that huge efforts are still necessary in modeling these important targets. To aid the ongoing efforts, we present a collection of online GPCR resources. 

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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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A list of Useful, Useless or simply Interesting facts on Proteins, Structures and what’s around them, generated by OCA: a browser and database for structure and function. Adopted from Proteopedia.

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