Electronic structure, binding energy, and solvation structure of the streptavidin-biotin supramolecular complex: ONIOM and 3D-RISM study.

We studied the electronic structure of the binding site of the streptavidin-biotin complex by using the ONIOM method at the HF/STO-3G:UFF level and obtained the solvation structure of the complex by using the statistical-mechanical, three-dimensional molecular theory of solvation (aka three-dimensional reference interaction site model, 3D-RISM-KH). All the streptavidin residues located within 3 A of the biotin residue were included in the quantum mechanical (QM) layer. In total, 16 residues including biotin with 274 atoms were in the QM layer, in which five residues are responsible for the hydrophobic interactions and nine residues for the hydrogen-bonding/electrostatic interaction with biotin. We found a geometry change of the urea moiety of the biotin bound in the network of van der Waals and polar interactions. Compared to the isolated biotin, the bridging C-C bond of the biotin urea moiety in the binding site increases in length as a result of the pi-sigma interaction with the surrounding streptavidin Trp residues. This extends the previous picture of the geometry change from the ureido group to the whole bicyclic urea moiety. We have evaluated the performance of 15 density functional methods and 11 basis sets by single point calculation for the binding energy of the optimized cooperative binding complex structure. Closest to the experimental value of 18.3 kcal/mol is the binding free energy of 19.6 kcal/mol obtained for the AN model at B3LYP/6-31G(d):UFF//HF/STO-3G:UFF level. The hybrid DFT methods with enhanced assessment for nonbonded interactions such as PBE1PBE, MPW1B95, and MPWB1K can also give accurate binding energy with the use of diffuse functionals (i.e., mPWB1K/6-31+G(d)). The 3D hydration structure of the unliganded streptavidin and the streptavidin-biotin complex obtained by using the 3D-RISM-KH molecular theory of solvation shows there is one immobilized water molecule at the biotin urea moiety, acting as a water bridge between the sulfur and the nitrogen of the NH group close to Ser45. This suggests that, in the docking process, biotin replaces six of the seven water molecules attached to the unliganded streptavidin binding site, and one remaining water molecule is squeezed into the gap between the Btn, Tyr43, Ser45, Trp92, and Trp79 residues in the binding pocket.