Molecular modeling of B-DNA site recognition by Ru intercalators: molecular shape selection

Abstract

In this work, molecular modeling methods have been applied to the interaction characterization of polypyridyl transitional-metal complexes with the oligonucleotide (B-DNA fragment). In order to explore the factors governing the groove recognition and intercalative depth, we establish a simple and practical docking method (step-by-step docking operation) to obtain potential curves while making complexes inset into B-DNA along an assigned path. Energy values in the potential curve are obtained from energy minimization of binding geometries. Modeling results clearly show that the optimum binding conformation corresponding to the global minimum in the potential curve for each complex is found to correlate well with the experimental results. Our results also confirm that minor changes of the ligand structure can lead to profound influences on binding geometries, so the molecular shape of the complexes is a predominant factor in governing the binding mode. Moreover, we find that the vdW force and "water molecular effect" are strongly associated with molecular-shape selection in our model. These results complement and extend the knowledge of the nature of these complexes binding to B-DNA.

Combined QM/MM and Classical Molecular Dynamics Study of [Ru(bpy)3]2+ in Water

“…Following the development of force-field parameters by the group of Norrby, 11 MM methods have been applied to the prediction of structures in the solid state 19 and in vacuum, 20 as well as to the study of the DNA intercalation of ruthenium polypyridyl compounds. 21,22 In this work, the solvation structure and dynamics of ruthenium tris-2,2′-bipyridine in aqueous solution have been investigated by means of DFT and TDDFT based QM/MM simulations in both ground and excited singlet MLCT states. Accurate statistics have been obtained by running purely classical simulations, which were validated by comparison with the QM/MM trajectory.…”

“…There are precedents in the literature for molecular mechanics (MM) treatments of ruthenium polypyridyl complexes. Following the development of force-field parameters by the group of Norrby, MM methods have been applied to the prediction of structures in the solid state and in vacuum, as well as to the study of the DNA intercalation of ruthenium polypyridyl compounds. , …”

Factors affecting nucleolytic efficiency of some ternary metal complexes with DNA binding and recognition domains. Crystal and molecular structure of Zn(phen)(edda)

“…The CD data and molecular modeling results above are without precedence when compared to metal complexes which have a slight preference for AT-rich regions of B-DNA [49]. Similar to ruthenium intercalators, the shape and the structure of the intercalating ligand and auxiliary ligand in M(phen)(edda) may be associated with their DNA binding selectivity [49].…”

“…Similar to ruthenium intercalators, the shape and the structure of the intercalating ligand and auxiliary ligand in M(phen)(edda) may be associated with their DNA binding selectivity [49]. However, the additional Jahn-Teller distortion factor seems to have subtle effect on modulating the shape and conformation of the M(phen)(edda) as exemplified by the higher binding fitness score of the Zn complex compared to the Cu complex in the docking simulation ( Table 3 pendant of the chelated L-arginine [22].…”