Refined models of coordination between Al3+/Mg2+ and enzyme in molecular dynamics simulation in terms of ABEEM polarizable force field.

MFX (AlF30, AlF4- and MgF3-) as transition state analogues of phosphoryl transfer enzymes (enzyme-MFX-TSAs) is of great significance for study of the catalytic mechanism of phosphoryl transfer enzymes. Bonded model and non-bonded model based on the ABEEM polarizable force field (ABEEM PFF) are developed and applied to study the coordination of enzyme-MFX-TSAs. The bond stretching of the bond containing metal is simulated by Morse potential energy function, because the change of chemical bond is described more accurately in a large range. The charge distribution of the system is distributed to multiple-charge-sites, including atomic site, σ bond site, π bond site and lone pair electron site. Partial charge can fluctuate according to the surrounding environment and molecular conformation. The reasonable charge distribution of 68 model molecules can be obtained, and the energy minimizations are performed in vacuum. Then, with the same parameters the charge distribution and the charge transfer of four complexes are obtained, and the energy minimization and molecular dynamics simulation in NVT ensemble are carried out in vacuum and explicit water solution. The results verify the correctness, rationality and transferability of the new parameters of ABEEM PFF, and the bonded model simulates more reasonable charge distribution and geometry. The parameters determined in this paper make up the blank of the parameters of MFX and phosophoryl transfer enzymes containing Mg2+. The development of ABEEM PFF provides a refined tool for MFX-TSAs to study the catalytic mechanism of phosphoryl transfer enzymes.

Systematic Parameterization and Simulation of Boronic Acid-ß-Lactamase Aqueous Solution in Developing the ABEEMσπ Polarizable Force Field.

Boronic acid, an inhibitor of ß-lactamase, has begun to be applied to the treatment of biological infections and tumors. Scientists are working to develop new and more effective boronic acid. Molecular dynamics (MD) simulation provides a powerful auxiliary tool for drug design. However, the current force fields have no boron-related parameters. In this work, an atom-bond electronegativity equalization method at the σπ level (ABEEMσπ) polarizable force field (ABEEMσπ PFF) of boronic acid and ß-lactamase has been developed to determine the potential functions and parameters. The interaction between boron and serine in ß-lactamase is regarded as a bonded mode. The interaction between them is simulated by the Morse potential energy function, which is close to the experimental change of the stretching potential energy in a large range. The potential energy surfaces of the bond length, bond angle, and dihedral angle of boronic acid-ß-lactamase have the same stability point and change trend as M06-2X/6-311G**. For 47 boronic acid-ß-lactamase training molecules, the linear correlation coefficient (R) of the charge distribution between the ABEEMσπ PFF and HF/STO-3G is greater than 0.96. Attributed to the fact that the charge distribution of the ABEEMσπ PFF can fluctuate with the change of geometry and environment, the polarization effect and charge-transfer effect are well reflected. The binding ability of different boronic acids with the same ß-lactamase is different. A total of 10 boronic acid-ß-lactamase model molecules and 10 boronic acid-ß-lactamase and water complexes are simulated. The order of binding energy of five large model molecules calculated by the ABEEMσπ PFF is consistent with that of the MP2 method. The binding energies of boronic acid-ß-lactamase and water complexes are close to those of the MP2 method. The results of MD simulation of five aqueous boronic acid-ß-lactamase complexes in the NVT ensemble verify the rationality of boron-related parameters of the ABEEMσπ PFF, which have a good application prospect. This study lays a solid theoretical foundation for further study of the inhibition of boronic acid on ß-lactamase.

ABEEM/MM OH- Models for OH-(H2O)n Clusters and Aqueous OH-: Structures, Charge Distributions, and Binding Energies.

Based on the atom-bond electronegativity equalization method fused into molecular mechanics (ABEEM/MM), two fluctuating charge models of OH--water system were proposed. The difference between these two models is whether there is charge transfer between OH- and its first-shell water molecules. The structures, charge distributions, charge transfer, and binding energies of the OH-(H2O)n (n = 1-8, 10, 15, 23) clusters were studied by these two ABEEM/MM models, the OPLS/AA force field, the OPLS-SMOOTH/AA force field, and the QM methods. The results demonstrate that two ABEEM/MM models can search out all stable structures just as the QM methods, and the structures and charge distributions agree well with those from the QM calculations. The structures, the charge transfer, and the strength of hydrogen bonds in the first hydration shell are closely related to the coordination number of OH-. Molecular dynamics simulations on the aqueous OH- solution are performed at 298 and 278 K using ABEEM/MM-I model. The MD results show that the populations of three-, four-, and five-coordinated OH- are 29.6%, 67.1%, and 3.4% at 298 K, respectively, and those of two-, three-, four-, and five-coordinated OH- are 10.8%, 44.9%, 39.2%, and 4.9% at 278 K, respectively; the average hydrogen bond lengths and the hydrogen bond angle in the first shell increase with the temperature decreasing.

Reaction mechanism of NO with hydrolysates of NAMI-A: an MD simulation by combining the QM/MM(ABEEM) with the MD-FEP method.

Nitrosylation reaction mechanisms of the hydrolysates of NAMI-A and hydrolysis reactions of ruthenium nitrosyl complexes were investigated in the triplet state and the singlet state. Activation free energies were calculated by combining the QM/MM(ABEEM) method with free energy perturbation theory, and the explicit solvent environment was simulated by an ABEEMσπ polarizable force field. Our results demonstrate that nitrosylation reactions of the hydrolysates of NAMI-A occur in both the triplet and the singlet states. The Ru-N-O angle of the triplet ruthenium nitrosyl complexes is in the range of 132.0°-138.2°. However, all the ruthenium nitrosyl complexes at the singlet state show an almost linear Ru-N-O angle. The nitrosylation reaction happens prior to the hydrolysis reaction for the first-step hydrolysates. The activation free energies of the nitrosylation reactions show that the H2 O-NO exchange reaction of [RuCl4 (Im)(H2 O)] in the singlet spin sate is the most likely one. Comparing with the activation free energies of the hydrolysis reactions of the ruthenium nitrosyl complexes, the results indicate that the rate of the DMSO-H2 O exchange reaction of [RuCl3 (NO)(Im)(DMSO)] is faster than that of [RuCl3 (H2 O)(Im)(DMSO)] in both the triplet spin state and the singlet spin state. © 2018 Wiley Periodicals, Inc.

Development of the ABEEMσπ Polarization Force Field for Base Pairs with Amino Acid Residue Complexes.

DNA damage caused by oxidized bases can lead to aging and cancer in living beings. Luckily, a repair enzyme is able to repair the oxidized bases. The key step is to accurately recognize the oxidized bases, which mainly rely on complex hydrogen bond interactions. We have calibrated the charge parameters and torsional parameters of the ABEEMσπ polarization force field (ABEEMσπ PFF) to accurately describe the intermolecular and intramolecular interactions. Taking the experiment and quantum chemical method as the benchmark, a series of properties of base pair-amino acid residue systems, DNA and DNA-protein interaction systems were calculated and compared with those of other force fields. We have done a tremendous amount of tasks in testing, calibrations, and analyses. The ABEEMσπ PFF not only explicitly gives the position and the partial charge of lone-pair electrons but also introduces a function kHB to fit special electrostatic interactions in hydrogen bond interaction regions. Therefore, it can accurately simulate the polarization effect and charge transfer of hydrogen bond interactions, especially for charged systems and sulfur-containing systems, such as the binding energy between amino acid and base pairs (24-28 kcal/mol), which is induced by charge transfer. The RMSD of ABEEMσπ PFF is 1.18 kcal/mol, whereas the RMSD of Amber OL15 is 8.21 kcal/mol. The relative positions of the amino acid residue have significantly changed, and the hydrogen bonds were broken when simulated by fixed charge force fields. In addition, owing to refitting the reasonable torsional parameters, the geometric structures optimized by ABEEMσπ PFF were well consistent with those of the M06-2X/6-311++G** method, but the simulations by fixed force fields have a large rotation of methyl and distortion of the plane of the base pair. After extensive MD simulation with four test DNAs and a DNA-protein system, we conclude that ABEEMσπ PFF shows better agreement when compared to experimental structures, which illustrates the reliability of our model and the transferability of the parameters.