Macromolecular Modeling Blog ™

Recently, as part of a structure based virtual screening campaign I’m undertaking, the following pose popped up as one of the highest ranking solutions:

Fluorine acts as an hydrogen bond acceptor in a predicted ligand pose

Wow, that’s a nice looking fluorine-hydrogen bond (C-F···H-X) with that Asparagine, I thought to myself. But wait, can fluorine act as an hydrogen bond acceptor? A quick google scholar search came up with the following (very highly cited) paper: “Organic Fluorine Hardly Ever Accepts Hydrogen Bonds“. In this work Dunitz and Taylor analyze structural data from the PDB and CSD and show that only rarely is fluorine found in appropriate distance to accept a proton:  Out of 5947 C-F bonds (in 1218 crystal structures in the CSD), only 37  (0.6%) are involved in possible C-F···H-X  hydrogen  bonds. For comparison, corresponding figures for C=O and N(Ar) (e.g. in pyridine) groups are 42% and 32%.

What about protein-ligand structures though? It is those that are of most interest to us. Back at the day (1997) Dunitz found only 14 protein-fluorine containing ligand complexes in the PDB and claimed that in these too fluorine rarely acts as an acceptor.

Looking for a more recent analysis, I remembered the very useful “A Medicinal Chemist’s Guide to Molecular Interactions” by Bissantz, Kuhn and Stahl in which they also touch upon halogen hydrogen bonds in protein-ligand complexes. To my surprise however, they take a completely opposite stand on the subject:

“Interactions between CF and polar hydrogen atoms HX (where X = O, N) frequently occur in the PDB and CSD, even if such interactions cannot be classified as strong hydrogen bonds.(ref. to the above Dunitz’s paper) We have observed a thrombin inhibitor to change its binding mode upon fluorination of an aryl ring, such that a CF···HN interaction is formed.(Ref.) In another study on factor VIIa inhibitors, a fluorinated phenyl ring was shown to act as an isostere of a pyridine.(Ref.) An increase of affinity from 455 to 68 nM was observed in sitagliptin analogues binding to DPP-IV when going from 3,4-difluorinated to 2,4,5-trifluorinated triazolopiperazines.(Ref.) The additional ortho-F forms interactions at 3.2 Å distance with NH2 groups of Asn and Arg side chains (PDB code 1×70)”.

Add to this collection of anecdotes a recent pico-molar inhibitor of Cytochrome bc(1) in which a tri-fluro-methyl group contributed a large chunk of affinity and was later shown to make hydrogen bonds in the crystal structure.

So what is the take home message? Does fluorine act a proton acceptor? Is it only in the context of protein-ligand complexes that it is able to form hydrogen bonds? Will you pick a compound predicted to form such an interaction for experimental validation? If you have an opinion vote in the poll below! If you have a reason, explanation or reference please share in the comments.

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Jack D. Dunitz, Robin Taylor (1997). Organic Fluorine Hardly Ever Accepts Hydrogen Bonds Chemistry – A European Journal DOI: 10.1002/chem.19970030115
Bissantz C, Kuhn B, & Stahl M (2010). A medicinal chemist’s guide to molecular interactions. Journal of medicinal chemistry, 53 (14), 5061-84 PMID: 20345171

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In the spirit of the 2012 Olympic games. Found at the webpage of the group of Prof. Heinz Neumann, Department for Molecular Structural Biology, Georg-August-University Göttingen. Anyone knows what protein is it?

Olympic Crystal Packing

HT to ravehb for the finding.

Three articles recently published in PLoS ONE are the harbinger of a RosettaCon 2010 PLoS one collection. How do you design a new enzyme from scratch? How do you model peptide binding with almost no prior information? And what puzzles CAN’T Rosetta solve?

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Some months ago, Bosco Ho, Molecular Dynamics (MD) boy wonder and HTML5 wiz, contacted a group of scientists, myself included, to start a world wide Journal Club (JC). The subject: Molecular Dynamics, the venue? Annotatr – a mashup of CiteULike and Disqus. The motivation behind Annotatr was to get scientists to comment on articles (lower the energy barrier if you prefer).

Since then the MD JC had several prolific sessions, discussing some great MD papers on which I’ll discuss briefly below, as well as recently, a completely unrelated theoretical evolutionary paper just to broaden our horizons.

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Bob Bateman* and Paul Craig** recently wrote an article entitled, “A Proficiency Rubric for Biomacromolecular 3D Literacy“, for the Education Corner of the PDB newsletter, where they presented three levels of 3D biomolecular literacy: Introductory Biology (novice level), Biochemistry/Cell Biology (amateur level) and Structural Biology Graduate Student (expert level). Together with Lea Michel** their goal is to develop structural biology educational resources for teaching, that will include assessment according to these rubrics.

As a first step, Bob, Paul and Lea are conducting a survey that addresses the uses of molecular visualization in education. The survey includes 11 multiple choice questions and 3 open ended questions. They have included comment boxes on many of the multiple choice questions in case there is not a choice or set of choices that accurately reflects your perspective. In that case, please indicate your choice in the comment box. We anticipate it will take your 15-25 minutes to complete.

Please take this short time to answer the survey (http://www.surveymonkey.com/s/62TL6ZJ) If the response to the survey is good, the plan is to compile the results and submit a manuscript to Biochemistry and Molecular Biology Education.

* Bob Bateman is a professor of biochemistry at the University of Southern Mississippi in Hattiesburg, Mississippi.

** Paul Craig and Lea Michel are professors in the Department of Chemistry at the Rochester Institute of Technology in Rochester, NY.

P.s. while you’re at it, you might want to revisit our poll on your favourite macromolecular viewer.

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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