Quantitative structure-activity relationship analyses on the free energy change during complex formation between substituted benzenesulfonamides (BSAs) and bovine carbonic anhydrase II (bCA II) were performed using generilized Born/surface area (GB/SA) and ab initio fragment molecular orbital (FMO) calculations for the whole complex structures. The result shows that the overall free energy change is governed by the contribution from solvation and dissociation free energy changes accompanying by complex formation. The FMO-IFIE (interfragment interaction energy) analysis quantitatively revealed that the intrinsic interaction energy of bCA II with BSAs is mostly from interactions with amino acid residues in the active site of bCA II. The "Zn block" (Zn(2+) and three histidine residues coordinated to Zn(2+)) in the active site shows the lowest interaction energy and the greatest variance of interaction energy with BSAs through their coordination interaction. The proposed procedure was demonstrated to provide a quantitative basis for understanding a ligand-protein interaction at electronic and atomic levels.

We carried out full ab initio molecular orbital calculations on complexes between neuraminidase-1 (N1-NA) in the influenza A virus and a series of eight sialic acid analogues including oseltamivir (Tamiflu) in order to quantitatively examine the binding mechanism and variation in the inhibitory potency at the atomic and electronic levels. FMO-MP2-IFIE (interfragment interaction energy at the MP2 level of ab initio fragment molecular orbital calculations) analyses quantitatively revealed (1) that the complex formation is driven by strong electrostatic interactions of charged functional groups in the analogues with ionized amino acid residues and water molecules in the active site of N1-NA, and (2) that the variation in the inhibitory potency among the eight analogues is determined by the dispersion and/or hydrophobic interaction energies of the 3-pentyl ether and charged amino moieties in oseltamivir with certain residues and water molecules in the active site of N1-NA. The current results will be useful for the development of new antiinfluenza drugs with high potency against various subtypes of wild-type and drug-resistant NAs.

The adhesion between epoxy resin and carbon fiber is investigated by using pair interaction energy decomposition analysis (PIEDA), by which the adhesive interaction energy and adhesive force can be partitioned into the electrostatic, exchange-repulsion, charge-transfer, and van der Waals (dispersion) contributions. The three stabilizing electrostatic, charge-transfer, and dispersion effects are correlated with the destabilizing exchange-repulsion effect. The surface structures of carbon fiber are modeled by the basal face, the armchair-edge structure, and the OH-functionalized armchair-edge structure of graphite. The surface of α-cristobalite (covered with OH groups), which can be viewed as a good model of a hydrophilic glass surface, is also studied. Adhesive properties of the model interfaces are evaluated on the basis of the binding energy of the resin with the carbon and glass surfaces and the adhesive force acting at the interfaces in terms of energy decomposition. PIEDA calculations demonstrate that only dispersion interactions can substantially work in the hydrophobic surfaces of the basal face and armchair-edge structures. This is a direct consequence of the electrostatic and charge-transfer interactions being cancelled by the exchange-repulsion interactions. On the other hand, both electrostatic and dispersion interactions are significant in the OH-functionalized surfaces of the armchair edge of graphite and α-cristobalite.

Based on the mutational effects on the steady-state kinetics of the electron transfer reaction and our NMR analysis of the interaction site (Sakamoto, K., Kamiya, M., Imai, M., Shinzawa-Itoh, K., Uchida, T., Kawano, K., Yoshikawa, S., and Ishimori, K. (2011) Proc. Natl. Acad. Sci. U.S.A. 108, 12271-12276), we determined the structure of the electron transfer complex between cytochrome c (Cyt c) and cytochrome c oxidase (CcO) under turnover conditions and energetically characterized the interactions essential for complex formation. The complex structures predicted by the protein docking simulation were computationally selected and validated by the experimental kinetic data for mutant Cyt c in the electron transfer reaction to CcO. The interaction analysis using the selected Cyt c-CcO complex structure revealed the electrostatic and hydrophobic contributions of each amino acid residue to the free energy required for complex formation. Several charged residues showed large unfavorable (desolvation) electrostatic interactions that were almost cancelled out by large favorable (Columbic) electrostatic interactions but resulted in the destabilization of the complex. The residual destabilizing free energy is compensated by the van der Waals interactions mediated by hydrophobic amino acid residues to give the stabilized complex. Thus, hydrophobic interactions are the primary factors that promote complex formation between Cyt c and CcO under turnover conditions, whereas the change in the electrostatic destabilization free energy provides the variance of the binding free energy in the mutants. The distribution of favorable and unfavorable electrostatic interactions in the interaction site determines the orientation of the binding of Cyt c on CcO. The electron transfer (ET)3 reactions in mitochondrial and bacterial respiratory chains are essential processes for energy transduction in cells. A series of ET reactions is terminated at cytochrome c oxidase (CcO), where molecular oxygen is reduced to water. Associated with the reduction of molecular oxygen, CcO functions as a proton pump across the membrane, and the proton gradient is the primary driving force for the generation of ATP (1-5).In the respiratory chain of mitochondria, the electrons to reduce molecular oxygen at CcO are donated from a small hemoprotein, cytochrome c (Cyt c), and Cyt c is thought to form an ET complex with CcO to promote the ET reaction from the heme iron in Cyt c to the Cu A site in CcO (6, 7). Although the reduction of molecular oxygen to water molecules requires four electrons, Cyt c can carry only one electron, implying that Cyt c repetitively associates with and dissociates from CcO and suggesting that the specific interprotein interactions between Cyt c and CcO regulate the binding affinity and the ET rate from Cyt c to CcO.The amino acid sequence and isoelectric point of Cyt c suggest that many positively charged residues are located on the protein surface (6, 7), as confirmed by solving the three-dimensional structures of Cyt c (8), allowing...

We carried out full ab initio fragment molecular orbital (FMO) calculations for complexes comprising human neuraminidase-2 (hNEU2) and sialic acid analogues including anti-influenza drugs zanamivir (Relenza) and oseltamivir (Tamiflu) in order to examine the variation in the observed inhibitory activity toward hNEU2 at the atomic and electronic levels. We recently proposed the LERE (linear expression by representative energy terms)-QSAR (quantitative structure-activity relationship) procedure. LERE-QSAR analysis quantitatively revealed that the complex formation is driven by hydrogen-bonding and electrostatic interaction of hNEU2 with sialic acid analogues. The most potent inhibitory activity, that of zanamivir, is attributable to the strong electrostatic interaction of a positively charged guanidino group in zanamivir with negatively charged amino acid residues in hNEU2. After we confirmed that the variation in the observed inhibitory activity among sialic acid analogues is excellently reproducible with the LERE-QSAR equation, we examined the reason for the remarkable difference between the inhibitory potencies of oseltamivir as to hNEU2 and influenza A virus neuraminidase-1 (N1-NA). Several amino acid residues in close contact with a positively charged amino group in oseltamivir are different between hNEU2 and N1-NA. FMO-IFIE (interfragment interaction energy) analysis showed that the difference in amino acid residues causes a remarkably large difference between the overall interaction energies of oseltamivir with hNEU2 and N1-NA. The current results will be useful for the development of new anti-influenza drugs with high selectivity and without the risk of adverse side effects.