The collaborative role of molecular conformation and energetics in the binding of gas-phase non-covalent polymer/amine complexes

A large series of similar non-covalent complexes were probed using ion mobility spectrometry, molecular mechanics/molecular dynamics (MM/MD), electrospray-tandem mass spectrometry (ESI-MS/MS) and RRKM theory in order to determine the effects of charge state and charge location upon the conformation, the 0 K activation energy (E(0)) and the entropy of activation (ΔS(?)) of the dissociation of these complexes. The non-covalent complexes consisted of poly(methylmethacrylate) oligomers and singly and doubly charged diaminoalkanes of varying length. This allowed for control of the charge separation within the complexes, as well as the size of the complex. A destabilizing effect was observed in complexes containing protons in close proximity, and/or short oligomers. Interestingly, a multiple charge stabilizing effect was observed when charge sites were sufficiently separated and/or when the polymer moiety of the complex was large. ΔS(?) values of doubly charged complexes showed a greater increase with increasing polymer size in comparison to singly charged complexes. This entropic observation is explained by structure, where IMS and MM/MD determined that the charge location was the determining factor of the overall conformation of these complexes and multiple charging resulted in more rigid arrangements. Dissociation of a tightly bound complex is more entropically favorable than a loosely bound complex. Also presented is a MM/MD refinement regime derived from IMS measurements.     

从对接结构中挑选近天然构象的新方法

分析了包含静电能(ΔEele)、去水化自由能(ΔGACE)以及范德华能(ΔEvdw)的打分函数在蛋白质－蛋白质对接中评价近天然构象的能力.对17种蛋白质复合物对接体系进行打分的结果表明，包含范德华能的打分函数（ΔEele＋ΔGACE＋ΔEvdw）比通常的打分函数（ΔEele、ΔGACE、ΔEele＋ΔGACE、ΔEele＋ΔEvdw、ΔGACE＋ΔEvdw）具有更好的区分近天然构象的能力.进一步的研究表明，优化（EM）对接体系后再进行打分，上面几种打分函数对对接结构的评价效果都有不同程度的改善，其中打分函数（ΔEele＋ΔGACE＋ΔEvdw）有更明显的改善.为了进一步确定候选结构中的近天然构象，以一种蛋白质复合物为例，对候选结构进行分子动力学（MD）模拟，根据MD轨迹中构象相对于初始构象的平方平均偏差（MSD）随时间的变化来辅助打分函数排除错误构象，得到了较好的结果.     

纤维素纤维接枝β-环糊精对苯二酚类分子的包络识别性能

用分光光度滴定法在不同温度、不同pH值条件下测定了纤维素纤维接枝β-环糊精与苯二酚类分子形成超分子包合物的表观热力学参数. 化学计量法表明, 纤维素纤维接枝β-环糊精上环糊精与客体苯二酚类分子形成了1∶1的超分子包合物. 从主-客体间包合物的表观热力学参数、尺寸关系、溶液pH值、包合时间等因素讨论了纤维上环糊精对客体苯二酚类分子的分子识别机制. 结果表明, 纤维素纤维接枝β-环糊精上环糊精对苯二酚类分子不同位置羟基具有分子选择性和识别能力.     

阳离子膨润土对分散染料的吸附动力学研究

研究了阳离子膨润土(EPI-DMA/Bt, PD/Bt, CTMAB/Bt)对分散染料(分散黄棕S-2RFL, 分散大红S-R, 分散蓝SBL, 分散黄SE-6GFL)的吸附动力学行为. 结果表明, 阳离子膨润土对分散染料的吸附过程符合二阶段吸附速率方程, 各阶段具有不同的吸附动力学常数(k1, k2)以及吸附活化能(Ea1, Ea2)、活化焓(ΔH*1, ΔH*2)和活化熵(ΔS*1, ΔS*2); 在阳离子膨润土对分散染料的吸附过程中, k1随着阳离子插层剂烷烃链的增加而增大, 表明较大的晶片层间距, 疏水的层间域和表面正电荷增加均有利于吸附速率增大; 对于两个吸附动力学阶段, ΔH★1<-TavΔS★1, △H★2<-TavΔS★2和ΔG★>0表明整个吸附过程活化熵的影响大于活化焓.     

Preparation,characterization of some transition metal complexes of hydrazone derivatives and their antibacterial and antioxidant activities

A new series of metal complexes of Pd(II), Cd(II) and Cu(II, I) of polydentate Schiff base ligand (H₂L), namely ((Z)-2-(phenylamino)-N'-(thiophen-2-ylmethylene) acetohydrazide) have been prepared. The ligand and its metal complexes have been characterized based on various physicochemical studies as elemental analyses, molar conductance, spectral (UV–Vis, MS, IR, ¹H NMR, ¹³C NMR and XRD), magnetic moment measurements and thermal studies (TG, DTG). In the view of previous studies, the ligand (H₂L) acts as polydentate one and coordinates with metal ions to form all metal complexes. The kinetic and thermodynamic parameters of decomposition process (ΔG, ΔH, ΔS) were calculated. The possible structures of the metal complexes have been computed using the molecular mechanic calculations using the hyper chem. 8.03 molecular modeling program. The calculations are performed to obtain the optimized molecular geometry. The antibacterial study of the selected compounds was assayed against two pathogenic bacteria. Moreover, the complexes (Cu II, I), Cd(II), Pd(II)) and the ligand revealed excellent antioxidant properties and could be useful in fighting the free radicals which occur in close connection with cancerous cells. It was remarkable that the two complexes (Cu II, I) demonstrated stronger antioxidant effects than their parent compounds. It is clear that the new complexes are good active compounds for use in a variety of applications.     

Ab initio QM/MM dynamics of H3O+ in water

A molecular dynamics (MD) simulation based on a combined ab initio quantum mechanics/molecular mechanics (QM/MM) method has been performed to investigate the solvation structure and dynamics of H3O+ in water. The QM region is a sphere around the central H3O+ ion, and contains about 6-8 water molecules. It is treated at the Hartree-Fock (HF) level, while the rest of the system is described by means of classical pair potentials. The Eigen complex (H9O4+) is found to be the most prevalent species in the aqueous solution, partly due to the selection scheme of the center of the QM region. The QM/MM results show that the Eigen complex frequently converts back and forth into the Zundel (H5O2+) structure. Besides the three nearest-neighbor water molecules directly hydrogen-bonded to H3O+, other neighbor waters, such as a fourth water molecule which interacts preferentially with the oxygen atom of the hydronium ion, are found occasionally near the ion. Analyses of the water exchange processes and the mean residence times of water molecules in the ion's hydration shell indicate that such next-nearest neighbor water molecules participate in the rearrangement of the hydrogen bond network during fluctuative formation of the Zundel ion and, thus, contribute to the Grotthuss transport of the proton.     

Demonstrating accuracy of the already proposed protocol for structure elucidation of cyclodextrin inclusion complexes by validation using quantitative ROESY analysis

In this study, we attempt to ascertain the accuracy of the structures determined using our previously developed method and hence the accuracy of our method. In the present report, we have taken the guest molecule cetirizine (CTZ) and the host molecules are α-cyclodextrin (α-CD) and β-cyclodextrin (β-CD). Structures with good accuracy were elucidated using a productive fusion of experimental and computational methods. We performed molecular mechanics studies (MM) in light of experimental ROESY studies, followed by molecular dynamics studies (MD). The results from these studies were analyzed using quantitative ROESY analysis to determine the final accurate structures of the complexes. The accuracy of these structures was tested using density functional theory (DFT) that is an accurate method for structure determination. DFT studies were carried out using the functionals B3LYP and M06L with def-TZVP basis set and similarly quantitative ROESY analysis was performed for the obtained structures. The ROESY intensities of the structures obtained from MM and MD studies, were compared with ROESY intensities of the structures obtained from DFT studies. Calculated ROESY intensities of the structures obtained from B3LYP functional are comparable, with intensities of structures obtained from MM and MD studies, but M06L functional showed poor results. In addition to the accuracy of MM and MD studies, low computational cost and less time input make it good method for structural studies for CD inclusion complexes.

     

Prediction of artifact peak intensity in linked scans for dissociations occurring in the first field-free region of sector mass spectrometers

Linked scans are commonly used on double-focusing mass spectrometers to obtain tandem mass spectrometry (MS/MS) spectra. The appearance of artifact peaks in linked scan MS/MS spectra from dissociations occurring in the first field-free region are a result of poor parent ion resolution, and they often can complicate the interpretation of the MS/MS spectra. The kinetic energy release associated with dissociation of ions of similar m/z to the “selected” parent ion is the main factor in determining the intensity of artifact peaks. A means of predicting the intensities of these artifact peaks in product ion and constant neutral loss scans is presented here. The method requires straightforward calculations based on Lacey-Macdonaldion intensity diagrams. The exact calculations require knowledge of the kinetic energy release of a particular dissociation, the kinetic energy spread of the main beam, and the parent ion and product ion mass-to-charge ratios. Adequate predictions, however, can be made by assuming a general kinetic energy release for any given reaction and a typical instrument energy resolution. Theoretical predictions are in good agreement with experimental data obtained from the product ion scans of unlabeled and isotopically labeled tirilazad and unlabeled and labeled leucine enkephalin methyl ester. There is also excellent agreement between experiment and theory in the constant neutral loss scans of rubidium bromide clusters.     

Low- and high-spin iron (II) complexes studied by effective crystal field method combined with molecular mechanics

A computational method targeted to Werner-type complexes is developed on the basis of quantum mechanical effective Hamiltonian crystal field (EHCF) methodology (previously proposed for describing electronic structure of transition metal complexes) combined with the Gillespie-Kepert version of molecular mechanics (MM). It is a special version of the hybrid quantum/MM approach. The MM part is responsible for representing the whole molecule, including ligand atoms and metal ion coordination sphere, but leaving out the effects of the d-shell. The quantum mechanical EHCF part is limited to the metal ion d-shell. The method reproduces with reasonable accuracy geometry and spin states of the Fe(II) complexes with monodentate and polydentate aromatic ligands with nitrogen donor atoms. In this setting a single set of MM parameters set is shown to be sufficient for handling all spin states of the complexes under consideration.     

A valence bond model for aqueous Cu(II) and Zn(II) ions in the AMOEBA polarizable force field

A general molecular mechanics (MM) model for treating aqueous Cu²⁺ and Zn²⁺ ions was developed based on valence bond (VB) theory and incorporated into the atomic multipole optimized energetics for biomolecular applications (AMOEBA) polarizable force field. Parameters were obtained by fitting MM energies to that computed by ab initio methods for gas‐phase tetra‐ and hexa‐aqua metal complexes. Molecular dynamics (MD) simulations using the proposed AMOEBA‐VB model were performed for each transition metal ion in aqueous solution, and solvent coordination was evaluated. Results show that the AMOEBA‐VB model generates the correct square‐planar geometry for gas‐phase tetra‐aqua Cu²⁺ complex and improves the accuracy of MM model energetics for a number of ligation geometries when compared to quantum mechanical (QM) computations. On the other hand, both AMOEBA and AMOEBA‐VB generate results for Zn²⁺–water complexes in good agreement with QM calculations. Analyses of the MD trajectories revealed a six‐coordination first solvation shell for both Cu²⁺ and Zn²⁺ ions in aqueous solution, with ligation geometries falling in the range reported by previous studies. © 2012 Wiley Periodicals, Inc.     

Complexation of N-methyl-4-(p-methyl benzoyl)-pyridinium methyl cation and its neutral analogue by cucurbit[7]uril and β-cyclodextrin: a computational study

In this work, molecular dynamics (MD) simulations have been conducted to study the inclusion complexes between cucurbit[7]uril (CB7) and β-cyclodextrin (β-CD) with N-methyl-4-(p-methyl benzoyl)-pyridinium methyl cation, and N-methyl-4-(p-methyl benzoyl)-pyridine in aqueous solutions to gain detailed information about the dynamics and mechanism of the inclusion complexes. The obtained MD trajectories were used to estimate the binding free energy of the studied complexes using the molecular mechanics/Poisson Bolzmann surface area (MM–PBSA) method. Results indicate preference of CB7 to bind to the cationic guest more than the neutral guest, whereas β-CD exhibits more or less the same affinity to complex with either species. Furthermore it was interesting to note that β-CD forms more stable complexes with both guests than CB7. Average structure of each complex and the distances between the center of masses of the guest and the host were also discussed.     

Quantum mechanics/molecular mechanics strategies for docking pose refinement: distinguishing between binders and decoys in cytochrome C peroxidase

We investigate the effect of systematically applying molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) to docked poses in an attempt to improve the correspondence between theoretical prediction and experimental observation. The proposed scheme involves running a short time scale MD simulation on a docked ligand pose (and any known structurally important crystal structure waters in the active site), followed by QM/MM minimization. Both of these steps are relatively fast for moderately sized ligands; longer time scale MD involving the protein is not found to improve the results. The final binding energy is given in terms of the QM/MM total energy, a van der Waals correction, and a term to account for desolvation effects. This methodology is first tested with a trypsin inhibitor, for which we establish the importance of running MD before reoptimizing with QM/MM. The method is then applied to cytochrome c peroxidase using a set of binders and decoys. In this example, the proposed methodology affords much better discrimination between binders and decoys than the traditional docking approach used. For both systems presented, application of this protocol results in a significantly better energetic ranking and a smaller root mean squared deviation from known crystallographic ligand poses. This work highlights the importance of including polarization effects through QM/MM and of sampling with MD to refine a set of initial docked poses.     

Accurate prediction of the enthalpies of formation for xanthophylls

This study investigates the applications of computational approaches in the prediction of enthalpies of formation (ΔH(f)) for C-, H-, and O-containing compounds. Molecular mechanics (MM4) molecular mechanics method, density functional theory (DFT) combined with the atomic equivalent (AE) and group equivalent (GE) schemes, and DFT-based correlation corrected atomization (CCAZ) were used. We emphasized on the application to xanthophylls, C-, H-, and O-containing carotenoids which consist of ～ 100 atoms and extended π-delocaization systems. Within the training set, MM4 predictions are more accurate than those obtained using AE and GE; however a systematic underestimation was observed in the extended systems. ΔH(f) for the training set molecules predicted by CCAZ combined with DFT are in very good agreement with the G3 results. The average absolute deviations (AADs) of CCAZ combined with B3LYP and MPWB1K are 0.38 and 0.53 kcal/mol compared with the G3 data, and are 0.74 and 0.69 kcal/mol compared with the available experimental data, respectively. Consistency of the CCAZ approach for the selected xanthophylls is revealed by the AAD of 2.68 kcal/mol between B3LYP-CCAZ and MPWB1K-CCAZ.     

Substrate hydroxylation in methane monooxygenase: quantitative modeling via mixed quantum mechanics/molecular mechanics techniques

Using broken-symmetry unrestricted density functional theory quantum mechanical (QM) methods in concert with mixed quantum mechanics/molecular mechanics (QM/MM) methods, the hydroxylation of methane and substituted methanes by intermediate Q in methane monooxygenase hydroxylase (MMOH) has been quantitatively modeled. This protocol allows the protein environment to be included throughout the calculations and its effects (electrostatic, van der Waals, strain) upon the reaction to be accurately evaluated. With the current results, recent kinetic data for CH3X (X = H, CH3, OH, CN, NO2) substrate hydroxylation in MMOH (Ambundo, E. A.; Friesner, R. A.; Lippard, S. J. J. Am. Chem. Soc. 2002, 124, 8770-8771) can be rationalized. Results for methane, which provide a quantitative test of the protocol, including a substantial kinetic isotope effect (KIE), are in reasonable agreement with experiment. Specific features of the interaction of each of the substrates with MMO are illuminated by the QM/MM modeling, and the resulting effects upon substrate binding are quantitatively incorporated into the calculations. The results as a whole point to the success of the QM/MM methodology and enhance our understanding of MMOH catalytic chemistry. We also identify systematic errors in the evaluation of the free energy of binding of the Michaelis complexes of the substrates, which most likely arise from inadequate sampling and/or the use of harmonic approximations to evaluate the entropy of the complex. More sophisticated sampling methods will be required to achieve greater accuracy in this aspect of the calculation.     

ATP与Mg2+、Ca2+生成配合物反应的热力学研究

The formation constant (K) and thermodynamic parameters (ΔC.ΔH.ΔS) in reactions in which complexes of adenosine triphosphate with magnesium ion and calcium ion are formed have been obtained by a microcalorimetric method. All experimentes were made at 30 ℃, pH=8.0 and at ionic strength μ=0.2 mol L~(-1). Measured experimental values indicate that complex formation reactions are driven by the entropic factor.     

Bivalent transition metal complexes of o-hydroxyacetophenone [N-(3-hydroxy-2-naphthoyl)] hydrazone: spectroscopic, antibacterial, antifungal activity and thermogravimetric studies

Schiff base complexes of Cu(II), Ni(II) and Zn(II) with the o-hydroxyacetophenone [N-(3-hydroxy-2-naphthoyl)] hydrazone (H(2)o-HAHNH) containing N and O donor sites have been synthesized. Both ligand and its metal complexes were characterized by different physicochemical methods, elemental analysis, molar conductivity ((1)H NMR, (13)C NMR, IR, UV-visible, ESR, MS spectra) and also thermal analysis (TG and DTG) techniques. The discussion of the outcome data of the prepared complexes indicates that the ligand behave as a bidentate and/or tridentate ligand. The electronic spectra of the complexes as well as their magnetic moments suggest octahedral geometries for all isolated complexes. The room temperature solid state ESR spectrum of the Cu(II) complex shows d(x2-y2) as a ground state, suggesting tetragonally distorted octahedral geometry around Cu(II) centre. The molar conductance measurements proved that the complexes are non-electrolytes. The kinetic thermodynamic parameters such as: E(#), ΔH(#), ΔG(#), ΔS(#) are calculated from the DTG curves, for the [Ni(H(O)-HAHNH)(2)] and [Zn(H(2O)-HAHNH)(OAc)(2)]·H(2)O complexes using the Coats-Redfern equation. Also, the antimicrobial properties of all compounds were studied using a wide spectrum of bacterial and fungal strains. The [Cu(Ho-HAHNH)(OAc)(H(2)O)(2)] complex was the most active against all strains, including Aspergillus sp., Stemphylium sp. and Trichoderma sp. Fungi; E. coli and Clostridium sp. Bacteria.     

Binding structures of tri‐N‐acetyl‐β‐glucosamine in hen egg white lysozyme using molecular dynamics with a polarizable force field

Lysozyme is a well‐studied enzyme that hydrolyzes the β‐(1,4)‐glycosidic linkage of N‐acetyl‐β‐glucosamine (NAG)_n oligomers. The active site of hen egg‐white lysozyme (HEWL) is believed to consist of six subsites, A‐F that can accommodate six sugar residues. We present studies exploring the use of polarizable force fields in conjunction with all‐atom molecular dynamics (MD) simulations to analyze binding structures of complexes of lysozyme and NAG trisaccharide, (NAG)₃. MD trajectories are applied to analyze structures and conformation of the complex as well as protein–ligand interactions, including the hydrogen‐bonding network in the binding pocket. Two binding modes (ABC and BCD) of (NAG)₃ are investigated independently based on a fixed‐charge model and a polarizable model. We also apply molecular mechanics with generalized born and surface area (MM‐GBSA) methods based on MD using both nonpolarizable and polarizable force fields to compute binding free energies. We also study the correlation between root‐mean‐squared deviation and binding free energies of the wildtype and W62Y mutant; we find that for this prototypical system, approaches using the MD trajectories coupled with implicit solvent models are equivalent for polarizable and fixed‐charge models. © 2012 Wiley Periodicals, Inc.