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Specific DNA recognition by the Antp homeodomain: MD simulations of specific and nonspecific complexes
Author(s) -
Gutmanas Aleksandras,
Billeter Martin
Publication year - 2004
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.20273
Subject(s) - dna , homeobox , molecular dynamics , macromolecule , biophysics , chemistry , hydrogen bond , antennapedia , point mutation , molecule , mutant , base pair , mutagenesis , intermolecular force , crystallography , biology , biochemistry , gene , computational chemistry , gene expression , organic chemistry
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. Proteins 2004. © 2004 Wiley‐Liss, Inc.