Abstract
Molecular dynamics (MD) simulations allow detail analysis of structural dynamics of atomic–level phenomena such as binding recognition fundamental in Biology field. Binding interaction involved between (bio) –molecules can be evaluated by binding free energy calculation base on the law of thermodynamics. Conformational flexibility essential for investigating dynamic property can be estimated by calculating conformational entropy such as principal components analysis. Combination with these techniques can provide reasonable explanations for atomic–level phenomena that are difficult to explain on the basis of static models alone. Here we present the results of a series of conventional MD simulations on recognition and interaction between (I) a mithramycin dimer and a DNA duplex, (II) several aminoglycoside antibiotics and an oligonucleotide corresponding to rRNA A–site. Both kinds of antibiotics consist of a core structure where several sugar ring substitutions at different carbon positions. In part I of the study, we successfully built the dynamics model corresponding to the experimental structure and binding affinity, discussed the binding interaction, and found the cooperativity between this GC–specific DNA binding antibiotic and a decanucleotide duplex of two GC binding sites to be in an anticooperative manner. Following the MD protocol and modification of the force field parameters for this sugar–linked antibiotic, in part II of the study, we compared the binding recognition and hydration patterns between several aminoglycoside antibiotics and a RNA duplex corresponding to the aminoacyl–tRNA decoding site (A–site) of the 16S rRNA on the 30S subunit which is a crucial component of the bacterial translational machinery. We have built several dynamic models with reasonable binding free energies showing good linear correlation with the experimental data. The hydration sites around the U1406·U1495 pair in the A–site were analyzed to distinguish tightly bound water molecules from fast–exchanging ones which has been suggested to be useful for rational drug design. We found that the hydration sites with long residence time identified between ring III of two 4,6–disubstituted antibiotics (tobramycin and kanamycin A) and phosphate oxygen atoms of G1405/U1406 may be worthy of further exploration for rational design of this kind.