Experimentally based contact energies decode interactions responsible for protein-DNA affinity and the role of molecular waters at the binding interface. Export

@article{citeulike:4537412, abstract = {A major obstacle towards understanding the molecular basis of transcriptional regulation is the lack of a recognition code for protein-DNA interactions. Using high-quality crystal structures and binding data on the promiscuous family of C(2)H(2) zinc fingers (ZF), we decode 10 fundamental specific interactions responsible for protein-DNA recognition. The interactions include five hydrogen bond types, three atomic desolvation penalties, a favorable non-polar energy, and a novel water accessibility factor. We apply this code to three large datasets containing a total of 89 C(2)H(2) transcription factor (TF) mutants on the three ZFs of EGR. Guided by molecular dynamics simulations of individual ZFs, we map the interactions into homology models that embody all feasible intra- and intermolecular bonds, selecting for each sequence the structure with the lowest free energy. These interactions reproduce the change in affinity of 35 mutants of finger I (R(2) = 0.998), 23 mutants of finger II (R(2) = 0.96) and 31 finger III human domains (R(2) = 0.94). Our findings reveal recognition rules that depend on DNA sequence/structure, molecular water at the interface and induced fit of the C(2)H(2) TFs. Collectively, our method provides the first robust framework to decode the molecular basis of TFs binding to DNA.}, author = {Temiz, N. Alpay and Camacho, Carlos J.}, citeulike-article-id = {4537412}, citeulike-linkout-0 = {http://dx.doi.org/10.1093/nar/gkp289}, citeulike-linkout-1 = {http://nar.oxfordjournals.org/cgi/content/abstract/37/12/4076}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19429892}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19429892}, day = {1}, doi = {10.1093/nar/gkp289}, issn = {1362-4962}, journal = {Nucleic acids research}, keywords = {protein\_dna}, month = {July}, number = {12}, pages = {4076--4088}, posted-at = {2009-05-18 11:10:14}, priority = {2}, title = {Experimentally based contact energies decode interactions responsible for protein-DNA affinity and the role of molecular waters at the binding interface.}, url = {http://dx.doi.org/10.1093/nar/gkp289}, volume = {37}, year = {2009} }

TY - JOUR ID - citeulike:4537412 L3 - citeulike-article-id:4537412 N2 - A major obstacle towards understanding the molecular basis of transcriptional regulation is the lack of a recognition code for protein-DNA interactions. Using high-quality crystal structures and binding data on the promiscuous family of C(2)H(2) zinc fingers (ZF), we decode 10 fundamental specific interactions responsible for protein-DNA recognition. The interactions include five hydrogen bond types, three atomic desolvation penalties, a favorable non-polar energy, and a novel water accessibility factor. We apply this code to three large datasets containing a total of 89 C(2)H(2) transcription factor (TF) mutants on the three ZFs of EGR. Guided by molecular dynamics simulations of individual ZFs, we map the interactions into homology models that embody all feasible intra- and intermolecular bonds, selecting for each sequence the structure with the lowest free energy. These interactions reproduce the change in affinity of 35 mutants of finger I (R(2) = 0.998), 23 mutants of finger II (R(2) = 0.96) and 31 finger III human domains (R(2) = 0.94). Our findings reveal recognition rules that depend on DNA sequence/structure, molecular water at the interface and induced fit of the C(2)H(2) TFs. Collectively, our method provides the first robust framework to decode the molecular basis of TFs binding to DNA. IS - 12 JF - Nucleic acids research SN - 1362-4962 EP - 4088 TI - Experimentally based contact energies decode interactions responsible for protein-DNA affinity and the role of molecular waters at the binding interface. VL - 37 SP - 4076 KW - protein_dna AU - Temiz, Alpay AU - Camacho, Carlos PY - 2009/07/01/ UR - http://dx.doi.org/10.1093/nar/gkp289 ER -