Structural changes in DNA upon binding in a 2:1 motif to a polyamide minor groove binder: f -IPP in 5'-TAGCTA-3'

摘要: Polyamide minor groove binders are known to disrupt cellular function when bound DNA. In this project, the structural changes of sequence 5'-TAGCTA-3', an important binding site for regulatory proteins in EGFR pathway, were investigated f-IPP using molecular dynamics simulations. Changes base-pair and base-pair-step parameters slide, twist, roll varied was added 5'-TAGCTA-3' system, causing DNA backbone stretch increase flexibility. Additionally, dihedral angles phosphate upon impacted global features that narrowed following addition. Introduction Minor Groove Binders their Cognate Sequences The segment is a cis-acting element or Epidermal Growth Factor Receptor (EGFR) pathway. 1 Specifically, recognized by transcription factor complex. If pathway not properly regulated, increased cell growth proliferation characteristic cancer may occur via STAT3 phosphorylation. 2 Targeting allows control complex so as encourage decrease undesired proliferation, therefore prevalent area study where new methods chemoprevention chemotherapy concerned. 3,4 will be utilized achieve targeting 5'-TAGCTA-3'. Analogues have been synthesized segments like 5'TAGCTA-3' relationship between biologically relevant sites influence on controlling aberrant gene expression. molecules constructed with high specificity affinity pre-determined sequences they targeting, mimicking behaviors DNA-binding proteins. 5 drugs netropsin distamycin A serve models type binder design. experiment, (Figure 1), generally binds way 2:1 anti-parallel drug/DNA motif 2). consist repeating pyrrole imidazole units modified successfully bind Selective achieved intentional selection ligand 2c). Figure 7 : chain structures promoter EGFR/STAT3. a) Example recognition pattern, b) modifications change c) identification. Note studied work modification one shown 2a has substituted pyrrole, thus it recognizes differs from 2a. To structure minor-groove Molecular Dynamics Simulations (MD) performed. Once complete, resulting analysis compared alone under same procedural conditions, serving foundation comparison. Structural Parameters MD uses classical Newtonian technique define force field 3) mathematically model dynamic behavior system studied. This time dependent, runs do exceed 50 ns. atoms, connectivity, positions, interparticle interactions defined, equations motion describe timedependent behavior. simulations instrumental characterization awhile, seen Ascona B-DNA Consortium. results these allow detailed visualization system's parameters. 3: 6 An example potential energy conformation obtained summations terms found field's functional form. Several used characterize binder. Such include zeta-epsilon angles, measurements depth width, alpha/gamma helical measurements. Torsion closely examined see how bonds atoms each nucleotide bend order arrive at its sequence. zeta (ζ) epsilon (e) specifically, 3). These torsion two Bonds: