First, I don't there are so many structures in PDB nowadays. "There were in total 1,031 crystal structures of protein–DNA complexes in the PDB as of 1 June 2008, in which the DNA was contacted by any amino-acid side chain at a distance less than 6.0 Å from base atoms."
Second, I don't know there are ways to do bioinformatics in 3D structure.
* Groove geometry was analysed using Curves (PMID: 2619933) and minor-groove width was calculated as a function of base sequence by averaging all the Curves levels given for each nucleotide.
* Hydrogen-bond contacts between amino-acid side chains and the DNA bases and phosphates, water molecules and other protein atoms were identified with the HBplus program (PMID: 8182748).
* Electrostatic potentials were obtained from solutions to the non-linear Poisson-Boltzman equation at 0.145 M salt using the DelPhi program.
Here is the paper I am referring to
Nature. 2009 Oct 29;461(7268):1248-53.
The role of DNA shape in protein-DNA recognition.
Rohs R, West SM, Sosinsky A, Liu P, Mann RS, Honig B.Howard Hughes Medical Institute, Center for Computational Biology and Bioinformatics, Department of Biochemistry and Molecular Biophysics, Columbia University, 1130 Saint Nicholas Avenue, New York, New York 10032, USA.
The recognition of specific DNA sequences by proteins is thought to depend on two types of mechanism: one that involves the formation of hydrogen bonds with specific bases, primarily in the major groove, and one involving sequence-dependent deformations of the DNA helix. By comprehensively analysing the three-dimensional structures of protein-DNA complexes, here we show that the binding of arginine residues to narrow minor grooves is a widely used mode for protein-DNA recognition. This readout mechanism exploits the phenomenon that narrow minor grooves strongly enhance the negative electrostatic potential of the DNA. The nucleosome core particle offers a prominent example of this effect. Minor-groove narrowing is often associated with the presence of A-tracts, AT-rich sequences that exclude the flexible TpA step. These findings indicate that the ability to detect local variations in DNA shape and electrostatic potential is a general mechanism that enables proteins to use information in the minor groove, which otherwise offers few opportunities for the formation of base-specific hydrogen bonds, to achieve DNA-binding specificity.
A lot of discussion on F1000
Suzanne Scarlata
Stony Brook University Medical Centre, United States of America
Pharmacology & Drug DiscoveryThe ability of proteins to recognize subtle differences in DNA sequences is not completely clear. Here, the authors show that arginine (Arg) residues can specifically insert into narrow minor grooves made from adenine (A)-tracts, uncovering a novel method of DNA recognition.
Compared to proteins, DNA has very few structural features, yet proteins can bind with amazing specificity. By comprehensively analyzing the structures of many protein-DNA complexes, Honig and coworkers find that A-thymine (AT)-rich sequences form a narrow minor groove with enhanced negative electrostatic potential. The result is a groove which has a surface that allows for strong interactions with Arg side chains. This mechanism appears to be used for many classes of DNA-binding proteins including nucleosomes, in which short DNA tracts containing A give rise to narrow grooves and allow for better stability of the coiled structure. The study also suggests that the preference of Arg side chains over lysine (Lys) side chains is not due to the better hydrogen-bonding potential of the guanidinium group, but it is due to the reduced amount of energy it costs to remove it from water as compared to an amine. Overall, this paper will allow for better search parameters to predict and understand protein-DNA binding.
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Jim Maher
Mayo Clinic College of Medicine, United States of America
Structural BiologyThe DNA minor groove often wasn't considered a very interesting place to be, until now. In this article, the authors reveal an electrostatic mode of DNA recognition occurring in the minor groove.
Conventional wisdom holds that most sequence-specific DNA recognition occurs by amino acid interactions in the large DNA major groove. Here are found hydrogen donor and acceptor patterns that are sequence-specific, allowing "direct readout" of the sequence by appropriate amino acid side chains. Besides being cramped, the hydrogen bonding information content of the minor groove is lower, making it difficult or impossible to gain detailed sequence information there. It is true that some natural products (netropsin, distamycin) and designed polyamides can achieve some sequence specificity in the minor groove, but the majority of sequence-specific DNA binding proteins "read" the major groove. By objective review of the growing crystal structure database for DNA and protein/DNA complexes, Rohs et al. add an interesting caveat. Certain DNA sequences (most notably A-tracts lacking T-A steps) have particularly narrow minor grooves. Theory and calculations show that DNA grooves in general, and unusually narrow minor grooves in particular, have the highest negative electrostatic potential on the DNA surface. Thus, it is not the phosphate backbone, but the grooves between backbones, that are the most favorable location for cations. Here, the authors note a unique propensity to find minor groove arginines from DNA binding proteins, which are preferred over lysines because of the lower dehydration cost of the former. The authors provide helpful examples, especially noting that histone contacts in the nucleosome appear to favor arginines that follow this principle. The work illustrates how objective mining of database information is still yielding new principles for how proteins indirectly recognize DNA sequences.
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Misha Sherman
The University of Texas Medical Branch, United States of America
Structural BiologyUsing bioinformatics, the authors found a new mechanism, widely used by DNA-binding proteins, of sequence-specific recognition of binding sites depending on DNA shape.
The novel mechanism is based on binding to the minor groove of DNA. The paper revealed a so-far-unanticipated strategy that many DNA-binding proteins use to find the correct spot to land onto the molecule, specifically its narrow minor groove. Amazingly, in 70% of the cases where the minor groove was narrower than 5 angstroms, they found arginine in close proximity to the nucleic acid. Although it is well accepted that proteins use sequence-specific hydrogen bonding in the major groove to recognize DNA sequences, in this paper the authors significantly widened our horizon of the ways in which proteins read information from DNA. Sequence-specific deformations of the DNA's three-dimensional shape are used by proteins to achieve specific DNA binding. In particular, proteins read the width of the minor DNA groove and associated electrostatic potential to enhance the specificity of the binding that is otherwise based upon the base-specific hydrogen bonds formed in the major groove. The authors found a strong correlation between AT-rich stretches in DNA (A-tracts) with a significantly narrowed minor groove and the preferred interaction of arginine with those sequences. Strong electrostatic interaction was noted there as well. They found a strong correlation between the width of the minor groove with stretches A-tracts of even three A or T-bases long, especially in cases without more flexible TpA steps. Interestingly, arginine is preferred over lysine in the interactions, most likely because of the more energetically costly transfer of lysine from water into the minor groove compared to arginine. The authors hypothesize that A-tracts that have the tendency to narrow the minor groove provide favorable binding sites for arginines, which, in turn, by inserting into the groove would stabilize the conformation leading to stable binding. The effect is evident in nucleosomes where there is a strong correlation between places where the backbone faces inward and the presence of short A-tracts with intrinsic propensity to assume bent conformations. Arginine insertion stabilizes the conformation even further.
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