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Specific DNA recogn...
Specific DNA recognition by the Antp homeodomain: MD simulations of specific and nonspecific complexes.
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- Gutmanas, Aleksandras (author)
- Gothenburg University,Göteborgs universitet,Svenskt NMR-centrum vid Göteborgs universitet,Swedish NMR Centre at Göteborg University
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- Billeter, Martin, 1955 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry
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(creator_code:org_t)
- 2004
- 2004
- English.
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In: Proteins. - : Wiley. - 1097-0134. ; 57:4, s. 772-82
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Abstract
Subject headings
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- Four molecular dynamics simulation trajectories of complexes between the wild-type or a mutant Antennapedia homeodomain and 2 DNA sequences were generated in order to probe the mechanisms governing the specificity of DNA recognition. The starting point was published affinity measurements showing that a single protein mutation combined with a replacement of 2 base pairs yields a new high-affinity complex, whereas the other combinations, with changes on only 1 macromolecule, exhibited lower affinity. The simulations of the 4 complexes yielded fluctuating networks of interaction. On average, these networks differ significantly, explaining the switch of affinity caused by the alterations in the macromolecules. The network of mostly hydrogen-bonding interactions involving several water molecules, which was suggested both by X-ray and NMR structures of the wild-type homeodomain and its DNA operator sequence, could be reproduced in the trajectory. More interestingly, the high-affinity complex with alterations in both the protein and the DNA yielded again a dynamic but very tight network of intermolecular interactions, however, attributing a significantly stronger role to direct hydrophobic interactions at the expense of water bridges. The other 2 homeodomain-DNA complexes, with only 1 molecule altered, show on average over the trajectories a clearly reduced number of protein-DNA interactions. The observations from these simulations suggest specific experiments and thus close the circle formed by biochemical, structural, and computational studies. The shift from a water-dominated to a more "dry" interface may prove important in the design of proteins binding DNA in a specific manner.
Subject headings
- NATURVETENSKAP -- Kemi -- Fysikalisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Physical Chemistry (hsv//eng)
Keyword
- Antennapedia Homeodomain Protein
- chemistry
- metabolism
- Base Sequence
- Computer Simulation
- Crystallography
- X-Ray
- DNA
- chemistry
- metabolism
- Macromolecular Substances
- Mutation
- genetics
- Nucleic Acid Conformation
- Protein Binding
- Substrate Specificity
- Time Factors
- Water
- chemistry
Publication and Content Type
- ref (subject category)
- art (subject category)
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