On the possible mode of regulation of DNA transcription by steroid hormones: Glucocorticoids

Journal of Biomolecular Structure and Dynamics

1992

Self Cite

Three-dimensional structures of complexes of 66 amino acid-DNA binding domains of human progesterone (hPR), estrogen (hER) and glucocorticoid (hGR) receptors (proteins), with ten base pair DNA duplexes: d(AGGTCATGCT).d(AGCATGACCT) and d(AGAACATGCT).d(AGCATGTTCT) were obtained using computer modeling and molecular mechanics techniques. Cartesian coordinates for the proteins were obtained from: 1) structural data of hER and hGR by NMR spectroscopy; 2) steric constraints imposed by tetrahedral coordination of the zinc ion to Cys residues, and 3) energy minimization in torsional and cartesian space. The proteins were made to interact with DNA (in B-form) in major groove through alpha-helical linker between the two zinc fingers. The geometry of the complexes was obtained by allowing them to slide, glide, penetrate in to and out of the groove, and to rotate about the helical axis. The complexes were energy minimized. Also maximized was the number of H-bonds between proteins and DNA. The complex structures were refined by molecular mechanics using AMBER 3.0. Structural parameters of DNA were analyzed in each complex and compared with those of native DNA optimized separately. The stereochemical differences of the complexes are discussed.

Section: Discussionmentioning

confidence: 98%

“…The steroid gives interaction energy of about -45 kcal/mole (36,37); the finger tip, about -70 kcal/mole (38). Interaction energy ofhelix-I was much lower energy ( -95 kcal/mole ).…”

Section: Discussionmentioning

confidence: 99%

Transcription Regulation by Steroid Hormones: A Computer Simulation Study

Journal of Biomolecular Structure and Dynamics

1992

Self Cite

“…Rotations were also allowed around the bond C9-N(al), CI2-CI5(a2), CI5-CI7 a3) within the drug and to some peptide side chains. The optimum position of the drug was obtained by energy minimisation using our package IMFI (40). The final complex was refined by MM using the force field described in the previous section on SAMD study.…”

Section: Complex Modelingmentioning

confidence: 99%

Computer Simulation of the Interaction of Non-steroidal Anti-inflammatory Drugs: Indoprofen and NS398 with Cyclooxygenase

Journal of Biomolecular Structure and Dynamics

Sahi

Srinivasan

1999

Self Cite

We have applied computer simulation technique to study interaction of two anti-inflammatory drugs (NSAIDs) indoprofen and NS398 with cyclooxygenase (COX-1 and COX-2) enzymes. We have also investigated conformational flexibility of the two drugs by systematic search and simulated annealing molecular dynamics (SAMD) methods. Both the drugs were docked in the cyclooxygenase channel using in house docking program IMF1. The complexes were energy minimised by molecular mechanics (MM) method. These were heated for 30 picoseconds (ps), equilibrated for 110 ps at 300K and subjected to 'production simulation' for 110 ps by molecular dynamics (MD) method using Sanderís module of AMBER 5.0 package and united atom force field mostly from PARM96.DAT. Integration was carried out with time step of 0.001 ps, distance dependent di-electric constant with scaling factor 2.0 for 1-4 interaction and cut-off distance for non-bonded pair-list equal to 8A. The non-bonded pair-list was upgraded after every 20 cycles. The coordinate output from MD trajectories is analysed using analysis package of AMBER 5.0, MOLMOL, P-CURVES 3.0 and in house packages: ANALMD, ANALP1. We have observed perturbative changes in COX-1 and COX-2 structures due to indoprofen and NS398. In case of indoprofen specific changes between COX-1 and COX-2 were noted in helix D, H6, S6 and helix H8 in the cyclooxygenase cavity. In case of NS398 these were in helix B in membrane binding domain, helix H6, S8 and S10 in cyclooxygenase cavity and helices H14-H16 in small lobe close to haem binding region. Implications of these results in enzyme selectivity by NSAIDs is discussed here.

“…(iii) The positively charged Zn 2÷ ion was introduced and the three fragments were arranged so as to yield tetrahedral coordination of SG, SG, NE2 and SG about it. The fragments were allowed to join smoothly by damped least square energy minimization (DLS) technique [12]. The refinement of the structures of seven fingers was achieved by Molecular Mechanics techniques using AMBER 3.0 [13] adopted for CYBER 180/930 system, using united atom force field parameters with distance dependent di-electric constant.…”

Section: Finger Simulationmentioning

confidence: 99%

Computer simulation of zinc finger motifs from cellular nucleic acid binding protein and their interaction with consensus DNA sequences

1990

FEBS Letters

We report here a computer simulation of the three-dimensional structures of seven zinc finger motifs from cellular nucleic acid binding protein involved in negative feedback inhibition of cholesterol biosynthesis. The structures are optimised using steric constraints imposed by tetrahedral coordination of the zinc ion with Cys and His residues, by molecular mechanics technique. We have also optimised the structure of a finger-I with GpT sequence. The model for the interaction of seven fingered protein with single-stranded d(GTGCGGTG) from sterol regulatory element (SRE) is given on the basis of these results. We also propose a scheme for recognition of a multifingered regulatory protein with small single-stranded DNA fragments.