MM CALCULATIONS OF THE METAL-PROTEIN MODEL COMPLEXES Ⅰ.MOLECULAR FORCE FIELD FOR COBALT COMPEXES

Cobalt-protein complexes play an important role in biochemical processes.The structure of the model molecule,Co(H_2O)_3SO_4(phen) has been studied by molecular mechanics.The molecular force field (MM2) parameters have been developed for the particular class of the complexes.

How Mutations Affecting the Ligand-receptor Interactions： a Combined MD and QM/MM Calculation on CYP2E1 and Its Two Mutants

Cytochrome P450（CYP） 2El is a dual function monoxygenase with a crucial role in the metabolism of 6% of drugs on the market at present. The enzyme is of tremendous interest for its association with alcohol consumption, diabetes, obesity and fasting. Despite the abundant experimental mutagenesis data, the molecular origin and the structural motifs for the enzymatic activity deficiencies have not been rationalized at the atomic level. In this regard, we have investigated the effects of mutation on the structural and energetic characteristics upon single point mutations in CYP2E1, N219D and $366C. The molecular dynamics（MD） simulation combined with quantum mechanics/molecular mechanics（QM/MM） and noncovalent interaction（NCI） analysis was carried out on CYP2EI and its two mutants. The results highlight the critical role of Phe207, which is responsible for both structural flexibility and energetic variation, shortening the gap between the theory and the experimentally observed results of enzymatic activity decrease, The underlying molecular mechanism of the enzymatic activity deficiencies for mutants may be attributed to the changes of spatial position of Phe207 in the two mutants. This work provides particular explanations to how mutations affect ligand-receptor interactions based on combined MD and QM/MM calculations. Furthermore, the mutational effects on the activity of CYP2E1 obtained in the present study are beneficial to both the experimental and the computational works of CYPs and may allow researchers to achieve desirable changes in enzymatic activity.

Conformational Study of 8-C-glucosyl-prunetin by Dynamic NMR Spectroscopy

By means of variable temperature NMR spectra, conformation of 8-C-glucosyl prunetin, isolated from the leaves of Dalbergia hainanensis (Leguminosae), was studied. The restricted rotation around the C (sp3)-C (sp2) bond in the C-glucosides isoflavonoid results in two main conformers (syn and anti). With the help of MM calculation, the preferred conformation A has H-1 gauche to the 7-OCH3. The barrier to rotation was 18.1 kcal/mol. This result agrees with the calculated value 16.2 kcal/mol of free energy of activation for the interconversion between the conformers.

On electrostatic interactions of adenosine triphosphate-insulin-degrading enzyme revealed by quantum mechanics/molecular mechanics and molecular dynamics

The insulin-degrading enzyme(IDE)plays a significant role in the degradation of the amyloid beta(Aβ),a peptide found in the brain regions of the patients with early Alzheimer’s disease.Adenosine triphosphate(ATP)allosterically regulates the Aβ-degrading activity of IDE.The present study investigates the electrostatic interactions between ATP-IDE at the allosteric site of IDE,including thermostabilities/flexibilities of IDE residues,which have not yet been explored systematically.This study applies the quantum mechanics/molecular mechanics(QM/MM)to the proposed computational model for exploring electrostatic interactions between ATP and IDE.Molecular dynamic(MD)simulations are performed at different temperatures for identifying flexible and thermostable residues of IDE.The proposed computational model predicts QM/MM energy-minimised structures providing the IDE residues(Lys530 and Asp385)with high binding affinities.Considering root mean square fluctuation values during the MD simulations at 300.00 K including heat-shock temperatures(321.15 K and 315.15 K)indicates that Lys530 and Asp385 are also the thermostable residues of IDE,whereas Ser576 and Lys858 have high flexibilities with compromised thermostabilities.The present study sheds light on the phenomenon of biological recognition and interactions at the ATP-binding domain,which may have important implications for pharmacological drug design.The proposed computational model may facilitate the development of allosteric IDE activators/inhibitors,which mimic ATP interactions.

The structure of 4-hydroxylphenylpyruvate dioxygenase complexed with 4-hydroxylphenylpyruvic acid reveals an unexpected inhibition mechanism

4-Hydroxyphenylpyruvate dioxygenase(HPPD)is an important target for both drug and pesticide discovery.As a typical Fe(II)-dependent dioxygenase,HPPD catalyzes the complicated transformation of 4-hydroxyphenylpyruvic acid(HPPA)to homogentisic acid(HGA).The binding mode of HPPA in the catalytic pocket of HPPD is a focus of research interests.Recently,we reported the crystal structure of Arabidopsis thaliana HPPD(At HPPD)complexed with HPPA and a cobalt ion,which was supposed to mimic the pre-reactive structure of At HPPD-HPPA-Fe(II).Unexpectedly,the present study shows that the restored At HPPD-HPPA-Fe(II)complex is still nonreactive toward the bound dioxygen.QM/MM and QM calculations reveal that the HPPA resists the electrophilic attacking of the bound dioxygen by the trim of its phenyl ring,and the residue Phe381 plays a key role in orienting the phenyl ring.Kinetic study on the F381 A mutant reveals that the HPPD-HPPA complex observed in the crystal structure should be an intermediate of the substrate transportation instead of the pre-reactive complex.More importantly,the binding mode of the HPPA in this complex is shared with several well-known HPPD inhibitors,suggesting that these inhibitors resist the association of dioxygen(and exert their inhibitory roles)in the same way as the HPPA.The present study provides insights into the inhibition mechanism of HPPD inhibitors.

Regioselective etherification of 1,2-O-isopropylidene-4,6-di-O-benzyl myo-inositol

During the etherification of 1,2-O-isopropylidene-4,6-di-O-benzyl myo-inositol, the specific regioselectivity on 3- or 8-hydroxyl group was showed to be determined by the nature of the O-alkylating agents used. As demonstrated by MM and MNDO calculation, the regioselectivity of the reaction mentioned can be rationalized by steric and/or electronic effect.