Knowledge-based elastic potentials for docking drugs with nucleic acids and applications in the study of DNA hydration and protein -DNA interactions

In this thesis, the patterns of water and amino acid atoms around nucleic acid bases, sugars, and phosphates have been collected and studied, and numerical methods have been developed to characterize and apply these patterns quantitatively.;Potential energy functions derived for the four common bases are tested by calculating the interaction energies of drug atoms from representative drug/DNA complexes with respect to derived ellipsoids around the four common bases. The predictions based on these energy functions are consistent with experimental data and confirm the mechanisms by which drug subunit pairs recognize the DNA base pairs as well as provide new insights into molecular interactions.;A rigid-body algorithm to dock drugs with DNA is introduced and subjected to two tests to determine its effectiveness and correctness, with docked drugs reproducing both the drug positions near the bases in oligonucleotide crystal structures and the preferred binding sites of drug association with the bases of nucleosomal DNA.;A novel flexible docking algorithm to dock drugs with DNA based on the rigid-body docking algorithm and the Powell search method is also introduced. Test results show that this algorithm is capable of finding the correct drug binding positions around the bases of DNA. DNA base-pair and drug structures predicted by this algorithm also closely resemble those in crystal structures.;The hydration and amino acid atom contact patterns around phosphate and deoxyribose groups are then collected and characterized. Ellipsoidal energy functions describing base, phosphate, and deoxyribose hydration or amino acid binding patterns have been overlapped with A- and B-form DNA fiber models, and the relationship between different hydration sites has been analyzed. More shared hydration sites are detected in A-DNA than in B-DNA and protein/DNA complexes, consistent with the known economics of A-DNA hydration.;Finally, the energetic characteristics and possible DNA-binding specificity factors of generic transcription factor/DNA complexes (with little DNA distorsions) and TBP/DNA complexes (with severely distorted DNA helices) have been studied, and different patterns of energetics and specificity determining factors were detected in the two samples.