Molecular Dynamics Studies of the Kinetics of Phase Changes in Clusters IV： Crystal Nucleation from Molten （NaCl）256 and （NaCl）500 Clusters

Molecular dynamics computer simulation based on the Born-Mayer-Huggins potential function has been carried out to study the effects of duster size and temperature on the nucleation rate of sodium chloride dusters in the temperature range of 580 K to 630 K. Clusters with 256 and 500 NaCl molecules have been studied and the results have been compared with those obtained from 108 molecule dusters. The melting point (MP) of the clusters were observed to increase with the size of the clusters and can be well described by a linear equation MP =1107(37)-1229(23)N^-1/3(N is the number of molecules in the duster).The nucleation rate was found to decrease with increasing the duster size or temperature. Various nucleation theories have been used to interpret the nucleation rates obtained from this molecular dynamics simulation. It is possible to use a constant diffuse interface thickness to interpret the nucleation rate from the diffuse interface theory in the temperature range of this study. However, the interfacinl free energy estimated from classical nucleation theory and diffuse interface theory increases too fast with increasing the temperature while that from Gran-Gunton theory does not change with changing temperatures.The sizes of critical nuclei estimated from all the theories are smaller than those estimated from our simulations.     

Amyloid Polymorphism in the Protein Folding and Aggregation Energy Landscape

Protein folding involves a large number of steps and conformations in which the folding protein samples different thermodynamic states characterized by local minima. Kinetically trapped on‐ or off‐pathway intermediates are metastable folding intermediates towards the lowest absolute energy minima, which have been postulated to be the natively folded state where intramolecular interactions dominate, and the amyloid state where intermolecular interactions dominate. However, this view largely neglects the rich polymorphism found within amyloid species. We review the protein folding energy landscape in view of recent findings identifying specific transition routes among different amyloid polymorphs. Observed transitions such as twisted ribbon→crystal or helical ribbon→nanotube, and forbidden transitions such helical ribbon?crystal, are discussed and positioned within the protein folding and aggregation energy landscape. Finally, amyloid crystals are identified as the ground state of the protein folding and aggregation energy landscape.     

一些有机物在RnTAC/SDS体系中的增溶及相转移自有能

三甲基氯化铵;阴阳离子表面活性剂复配;一些有机物在RnTAC/SDS体系中的增溶及相转移自有能     

谷氨酰胺结合蛋白的分子动力学模拟和自由能计算

谷氨酰胺结合蛋白(Glutamine-binding protein, GlnBp)是大肠杆菌透性酶系统中一个细胞外液底物专一性结合蛋白, 对于细胞外液中谷氨酰胺(Gln)的运输和传递至关重要. 本文运用分子动力学(Molecular dynamics, MD)模拟采样, 考察了GlnBp关键残基与底物Gln之间的相互作用和GlnBp两条铰链的功能差别; 并采用MM-PBSA方法计算了GlnBp与底物Gln的结合自由能. 结果表明: Ph13, Phe50, Thr118和Ile69与底物Gln的范德华相互作用和Arg75, Thr70, Asp157, Gly68, Lys115, Ala67, His156与底物Gln的静电相互作用是结合Gln的主要推动力; 复合物的铰链区85～89柔性大, 对构象开合提供了结构基础; 而铰链区181～185柔性小, 其作用更多是在功能上把底物Gln限制在口袋中; 自由能预测值与实验值吻合. 本研究很好地解释了GlnBp结构与功能的关系, 为进一步了解GlnBp的开合及转运Gln的机制提供了重要的结构信息.     

烷基芳基磺酸盐的分子动力学模拟与自由能微扰计算

为研究不同结构的表面活性剂分子在溶液中胶束化能力的差异, 采用分子动力学方法模拟三种烷基芳基磺酸盐在真空和水溶液环境下的结构与相互作用. 利用自由能微扰(FEP)方法计算了水合自由能, 发现与用传统热力学表面张力法测定自制的烷基芳基磺酸盐结果一致. 研究表明: 烷基芳基磺酸盐在水溶液中的胶束化过程是自发进行的, 随着分子结构中芳环向长烷基链中间位置移动, 胶束化能力和胶束稳定性均下降; 疏水基周围水分子的“冰山结构”会影响胶束的稳定性, 而水分子中氢键的生存周期是反映冰山结构变化的重要指标; 同时, 亲水基与水分子间形成氢键的数目会增强或减弱分子脱离胶束体的趋势, 从而影响胶束结构的稳定性.     

低自由能固体表面的制备及其应用*

低自由能表面具有一些独特的性能,在工业和日常生活中具有广泛的应用,本文就低自由能表面的制备及其发展概况进行综述,共引用文献83篇。     

Oversampling Free Energy Perturbation Simulation in Determination of the Ligand-Binding Free Energy

Determination of the ligand-binding affinity is an extremely interesting problem. Normally, the free energy perturbation (FEP) method provides an appropriate result. However, it is of great interest to improve the accuracy and precision of this method. In this context, temperature replica exchange molecular dynamics implementation of the FEP computational approach, which we call replica exchange free energy perturbation (REP) was proposed. In particular, during REP simulations, the system can easily escape from being trapped in local minima by exchanging configurations with high temperatures, resulting in significant improvement in the accuracy and precision of protein–ligand binding affinity calculations. The distribution of the decoupling free energy was enlarged, and its mean values were decreased. This results in changes in the magnitude of the calculated binding free energies as well as in alteration in the binding mechanism. Moreover, the REP correlation coefficient with respect to experiment ( R^REP = 0.85 ± 0.15 ) is significantly boosted in comparison with the FEP one ( R^FEP = 0.64 ± 0.30 ). Furthermore, the root-mean-square error (RMSE) of REP is also smaller than FEP, RMSE^REP = 4.28 ± 0.69 versus RMSE^FEP = 5.80 ± 1.11 kcal/mol, respectively. © 2019 Wiley Periodicals, Inc.     

Aggregation of sodium dodecyl sulfate in aqueous sodium chloride solutions

Summary Aqueous solutions of sodium dodecyl sulfate with added sodium chloride (0–0.3 mol kg^–1) were studied at 298.2 K in order to calculate the molar standard free energy of micelle formationG _m . The following properties were measured: (i) aggregation number by membrane osmometry, (ii) counter-ion binding and sodium ion activities by electromotive force, (iii) critical micelle concentration by electromotive force and fluorescence spectrophotometry. The results indicate thatG _m . is independent of the NaCl concentration.     

Inhibition Mechanism of Hydroxyproline-like Small Inhibitors to Disorder HIF-VHL Interaction by Molecular Dynamic Simulations and Binding Free Energy Calculations

Protein-protein interactions are vital for a wide range of biological processes. The interactions between the hypoxia-inducible factor and von Hippel Lindau (VHL) are attractive drug targets for ischemic heart disease. In order to disrupt this interaction, the strategy to target VHL binding site using a hydroxyproline-like (pro-like) small molecule has been reported. In this study, we focused on the inhibition mechanism between the pro-like inhibitors and the VHL protein, which were investigated via molecular dynamics simulations and binding free energy calculations. It was found that pro-like inhibitors showed a strong binding affinity toward VHL. Binding free energy calculations and free energy decompositions suggested that the modification of various regions of pro-like inhibitors may provide useful information for future drug design.     

Comparison of Penta and Tetra-pyridyl Cobalt-based Catalysts for Water Reduction: H2 Production Cycle,Solvent Response and Reduction Free Energy

Understanding water reduction towards H₂ generation is crucial to overcome today's renewable energy obstacles. Previous studies have shown the superior H₂ production performances of Cobalt based penta-pyridyl (CoaPPy) and tetra-pyridyl (CoaTPy) complexes in solution. We investigate H₂ production cycles of CoaPPy and CoaTPy complexes immersed in water solution by means of Ab-initio Molecular Dynamics and Density Functional Theory. We monitor dynamic properties of the systems, solvent response and structural changes occurring in the catalysts, by simulating all intermediate steps of the H₂ production cycle. Reduction free energies and reorganization energies are calculated. Our results show that, following the first electron injection, H₂ production proceeds with the singlet spin state. Following the first electron insertion, we observe a significant rearrangement of the hydrogen bonding network in the first solvation shell. The cobalt center turns out to be more accessible for the surrounding water molecules in the case of CoaTPy at all the intermediate steps, which explains its higher catalytic performance over CoaPPy. Following the first reduction reaction, a larger gain in reduction free energy is estimated for CoaTPy with respect to CoaPPy, with a difference of 0.14 eV, in line with the experiments. For the second reduction, instead, CoaPPy shows more negative reduction potential, by 0.41 eV.     

Absolute Protein Binding Free Energy Simulations for Ligands with Multiple Poses,a Thermodynamic Path That Avoids Exhaustive Enumeration of the Poses

We propose a free energy calculation method for receptor–ligand binding, which have multiple binding poses that avoids exhaustive enumeration of the poses. For systems with multiple binding poses, the standard procedure is to enumerate orientations of the binding poses, restrain the ligand to each orientation, and then, calculate the binding free energies for each binding pose. In this study, we modify a part of the thermodynamic cycle in order to sample a broader conformational space of the ligand in the binding site. This modification leads to more accurate free energy calculation without performing separate free energy simulations for each binding pose. We applied our modification to simple model host–guest systems as a test, which have only two binding poses, by using a single decoupling method (SDM) in implicit solvent. The results showed that the binding free energies obtained from our method without knowing the two binding poses were in good agreement with the benchmark results obtained by explicit enumeration of the binding poses. Our method is applicable to other alchemical binding free energy calculation methods such as the double decoupling method (DDM) in explicit solvent. We performed a calculation for a protein–ligand system with explicit solvent using our modified thermodynamic path. The results of the free energy simulation along our modified path were in good agreement with the results of conventional DDM, which requires a separate binding free energy calculation for each of the binding poses of the example of phenol binding to T4 lysozyme in explicit solvent. © 2019 Wiley Periodicals, Inc.     

葡萄糖苷酶抑制剂作用机理的分子动力学模拟和自由能计算

含有锍离子的葡萄糖苷酶抑制剂如kotalanol (SK)和它除去磺酸基团后的衍生物(DSK), 是潜在的毒副作用较小的治疗II 型糖尿病的候选药物. α-葡萄糖苷酶抑制活性实验显示, DSK活性比SK略高, 而将二者环上的S原子替换成NH后(分别称为DSN和SN), DSN的活性要比SN高1500倍左右. 本文用分子动力学模拟, 结合自由能计算和自由能分解的方法对上述四个抑制剂的作用机理进行了研究. 研究结果表明活性的巨大差异是由NH基团取代效应和磺酸基团立体效应共同作用的结果, 由于N―C键长比S―C键长短, NH基团取代导致烷基链的翻转, 同时, 磺酸基团限制了链的翻转, 因此改变了抑制剂的结合模式. 计算结果与实验基本一致.本文的研究结果有助于进一步理解含锍离子的葡萄糖苷酶抑制剂的结合机理, 并为设计更有潜力的葡萄糖苷酶抑制剂提供了有价值的信息.     

Hydrogen-Bond Free Energy of Local Biological Water

Here, we propose an experimental methodology based on femtosecond-resolved fluorescence spectroscopy to measure the hydrogen (H)-bond free energy of water at protein surfaces under isothermal conditions. A demonstration was conducted by installing a non-canonical isostere of tryptophan (7-azatryptophan) at the surface of a coiled-coil protein to exploit the photoinduced proton transfer of its chromophoric moiety, 7-azaindole. The H-bond free energy of this biological water was evaluated by comparing the rates of proton transfer, sensitive to the hydration environment, at the protein surface and in bulk water, and it was found to be higher than that of bulk water by 0.4 kcal mol⁻¹. The free-energy difference is dominated by the entropic cost in the H-bond network among water molecules at the hydrophilic and charged protein surface. Our study opens a door to accessing the energetics and dynamics of local biological water to give insight into its roles in protein structure and function.     

Molecular Dynamics Studies of the Kinetics of Phase Changes in Clusters II: Crystal Nucleation from Molten (RbCl)256 and (RbCl)500 Clusters

Molecular dynamics computer simulations have been carried out to study the effects of cluster size and temperature on the nucleation rate of rubidium chloride clusters in the temperature range of 500-650 K. Clusters with 256 and 500 RbCl molecules have been studied and the results are compared with those obtained from 108 molecule clusters. The melting point (MP) of the clusters was observed to increase with the size of the clusters and can be described by a linear equation MP=997-405 N^−1/3, where N is the number of molecules in the cluster. The nucleation rate is found to decrease with increasing cluster size or increasing nucleation temperature. Both classical nucleation theory and diffuse interface theory are used to interpret our observed results.     

Insights on Aggregation of Hen Egg-White Lysozyme from Raman Spectroscopy and MD Simulations

Protein misfolding and aggregation play a significant role in several neurodegenerative diseases. In the present work, the spontaneous aggregation of hen egg-white lysozyme (HEWL) in an alkaline pH 12.2 at an ambient temperature was studied to obtain molecular insights. The time-dependent changes in spectral peaks indicated the formation of β sheets and their effects on the backbone and amino acids during the aggregation process. Introducing iodoacetamide revealed the crucial role of intermolecular disulphide bonds amidst monomers in the aggregation process. These findings were corroborated by Molecular Dynamics (MD) simulations and protein-docking studies. MD simulations helped establish and visualize the unfolding of the proteins when exposed to an alkaline pH. Protein docking revealed a preferential dimer formation between the HEWL monomers at pH 12.2 compared with the neutral pH. The combination of Raman spectroscopy and MD simulations is a powerful tool to study protein aggregation mechanisms.     

基于分子动力学模拟和连续介质模型的自由能计算方法*

近些年,基于分子动力学模拟和连续介质模型的自由能计算方法受到了越来越多的关注,其中MM/PBSA就是最具代表性的方法.在MM/PBSA中,体系的焓变采用分子力学(MM)的方法计算得到;溶剂效应中极性部分对自由能的贡献通过解Poisson-Boltzmann(PB)方程的方法计算得到;溶液效应中非极性部分对自由能的贡献则通过分子表面积(SA)计算得到.本文结合我们科研组的工作,就近几年MM/PBSA方法的最新进展做了较为详细的阐述,同时对MM/PBSA的发展前景进行了展望.     

CDK2-抑制剂结合自由能计算

细胞周期蛋白依赖性激酶Ⅱ(cyclin-dependent kinase 2,CDK2)是一种重要的治疗癌症的靶标.本文中采用分子动力学取样,运用MM-PBSA/GBSA两种方法计算了CDK2-NU6102复合物的绝对结合自由能.通过能量分解的方法考察了CDK2大分子主要残基与配体NU6102之间的相互作用和识别.     

配位化学中的直线自由能关系(XIX)

前文[1]曾报导了侧基二氧四胺大环配体的合成及表征．与普通配合物相比，大环多胺配合物具有较高的稳定性及惰性和奇特的空间构型，其过渡金属配合物具有特殊的性质和用途，如作酶的模型、氧的载体等．铜（Ⅱ）配合物可作超氧歧化酶（SOD）的模型，超氧离子是人体内的氧代谢产物，它在体内过量积累会引起多种疾病，超氧歧化酶对超氧离子起催化歧化作用，以维持机体的正常运行间，故这种大环多胺Cu（Ⅱ）配合物具有重要的生物功能及广阔的应用前景．本文研究了四种带侧基二氧四胺大环配体-5-取代邻菲罗啉（5－Xphen；L1）铜（Ⅱ）三元配合…     

Activity coefficients in aqueous NaCl−CsCl2 mixtures from solubility data up to 75°C: A supplement to Pitzer's work

Activity coefficients of NaCl in aqueous NaCl-CsCl₂ mixtures in the CaCl₂ rich region at 25, 50 and 75°C were calculated from recent solubility data of Chou and his group. The results are compared with those obtained from ion-interaction equations using solution data of de Lima and Pitzer, who had also reported similar comparisons but using the inconsistent solubility data of Plyushchev et al. The agreement obtained between the Chou solubility data and the Pitzer equation is excellent.