Macromolecular Modeling Blog ™

In a recent post in “Discount Thoughts” Michael Clarkson reviews a paper examining the dynamics of allostery in PBX1 homeodomain. Another example for a possible conformational selection binding mechanism.

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As usual, a long absence means two things, lots of work to do, and lots of papers to read. You can find here our pickings from the recent literature. Enjoy.

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There are several forms of peptide-protein interactions, one of which are globular PPIs mediated by a dominant linear peptide at the interface. To what extent could peptides extracted from a globular protein monomer be used to inhibit the interaction to its partner? In this work, we have investigated the possibility of deriving peptides from the interface of globular proteins to design inhibitors that would compete with their native interaction.
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We present Rosetta FlexPepDock, a novel tool for refining coarse peptide–protein models that allows significant changes in both peptide backbone and side chains. We obtain high resolution models, often of sub-angstrom backbone quality, over an extensive and general benchmark of 89 peptide–protein interactions.

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How can peptides overcome the entropic cost involved in switching from an unstructured, flexible peptide to a rigid, well-defined bound structure? What are the strategies used by peptides in? order to bind their protein receptor? How is this different than protein-protein interactions? In this work we performed A structure-based analysis of peptide-protein interactions to try and answer these questions.

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Peptide-protein interactions are a key component of the cellular protein-protein interaction network. These interactions, in which one partner is a globular protein (or domain) and the other is a flexible linear peptide are very prevalent, and play a role in major cellular processes, predominantly in signaling and regulatory networks. Due to their abundance and cardinal role in regulatory interactions, flexible peptides are in many cases implicated in human disease and cancer. Consequently, peptide-protein interactions are gaining much interest of late. The Furman group have recently published a series of papers on the subject of peptide-protein interactions (disclaimer – these were partly authored by yours truly). In this post I will introduce the subject and the motivation to investigate these interactions and in later posts of this ‘mini-series’ I will get into more details on this on-going research.
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A collection of interesting papers from the recent literature – there’s something for everyone here. Enjoy.

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About a year ago we reported of PLoS and Molsoft launching a new way of publishing structural biology related papers. A couple of days ago I’ve stumbled on one such paper, published in PLoS biology and decided to take the technology for a ride.

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In a recent post, Derek Lowe, from “In The Pipeline”, asks his readership “If we could just walk right up and calculate the free energies of binding events reliably, what would you most want such calculations to be able to do for you? What would convince you that they’re actually believable? And how close to you think that we actually are to that?” We tried to briefly answer some of these questions. How close are we to predict small molecules binding free energy?

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How do enzymes catalyze reactions? There are countless answers of course, but one answer that has gained much attention and popularity in recent years is – through intrinsic dynamics. Is that so? PNAS recently published a paper by Arieh Warshel entitled: “Enzyme millisecond conformational dynamics do not catalyze the chemical step”. Warshel, an avid assailant of the coupling between dynamics and catalysis was met by Martin Karplus, devoted advocate for catalytic dynamics, to engage in a public dispute over the letters section of PNAS. Who do you find more convincing?

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