Test of athermal terms of activity coefficient models by Monte Carlo simulation with hard-core models

The infinite dilution activity coefficients of exactly athermal fluids were calculated by Monte Carlo simulation with hard-core models. The hard-core models used in this work were hard-sphere and hard-spherocylinder models. The Widom test particle method was adopted to calculate the residual chemical potentials of solutes in pure solvent and in pure solute solutions. The infinite dilution activity coefficients of solutes were obtained from the residual chemical potentials of solutes. The infinite dilution activity coefficients calculated by Monte Carlo simulation were compared with those of athermal terms in activity coefficient equations. Staverman–Guggenheim equation overestimates the activity coefficients. The deviations of activity coefficients increase with increasing the hard-core volume of solute. Flory–Huggins equation based on molar volume gives good results for the hard-spherocylinder systems. Elbro-FV equation gives good results for both the hard-sphere and hard-spherocylinder systems.     

Mechanism of the decrease in catalytic activity of human cytochrome P450 2C9 polymorphic variants investigated by computational analysis

Cytochrome P450 (CYP) is deeply involved in the metabolism of chemicals including pharmaceuticals. Therefore, polymorphisms of this enzyme have been widely studied to avoid unfavorable side effects of drugs in chemotherapy. In this work, we performed computational analysis of the mechanism of the decrease in enzymatic activity for three typical polymorphisms in CYP 2C9 species: *2, *3, and *5. Based on the equilibrated structure obtained by molecular dynamics simulation, the volume of the binding pocket and the fluctuation of amino residues responsible for substrate holding were compared between the wild type and the three variants. Further docking simulation was carried out to evaluate the appropriateness of the binding pocket to accommodate substrate chemicals. Every polymorphic variant was suggested to be inferior to the wild type in enzymatic ability from the structural viewpoint. F‐G helices were obviously displaced outward in CYP2C9*2. Expansion of the binding pocket, especially the space near F′ helix, was remarkable in CYP2C9*3. Disappearance of the hydrogen bond between K helix and β4 loop was observed in CYP2C9*5. The reduction of catalytic activity of those variants can be explained from the deformation of the binding pocket and the consequent change in binding mode of substrate chemicals. The computational approach is effective for predicting the enzymatic activity of polymorphic variants of CYP. This prediction will be helpful for advanced drug design because calculations forecast unexpected change in drug efficacy for individuals. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Basic ingredients of free energy calculations: A review

Methods to compute free energy differences between different states of a molecular system are reviewed with the aim of identifying their basic ingredients and their utility when applied in practice to biomolecular systems. A free energy calculation is comprised of three basic components: (i) a suitable model or Hamiltonian, (ii) a sampling protocol with which one can generate a representative ensemble of molecular configurations, and (iii) an estimator of the free energy difference itself. Alternative sampling protocols can be distinguished according to whether one or more states are to be sampled. In cases where only a single state is considered, six alternative techniques could be distinguished: (i) changing the dynamics, (ii) deforming the energy surface, (iii) extending the dimensionality, (iv) perturbing the forces, (v) reducing the number of degrees of freedom, and (vi) multi‐copy approaches. In cases where multiple states are to be sampled, the three primary techniques are staging, importance sampling, and adiabatic decoupling. Estimators of the free energy can be classified as global methods that either count the number of times a given state is sampled or use energy differences. Or, they can be classified as local methods that either make use of the force or are based on transition probabilities. Finally, this overview of the available techniques and how they can be best used in a practical context is aimed at helping the reader choose the most appropriate combination of approaches for the biomolecular system, Hamiltonian and free energy difference of interest. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

A molecular mechanics model for imatinib and imatinib:kinase binding

Imatinib is an important anticancer drug, which binds specifically to the Abl kinase and blocks its signalling activity. To model imatinib:protein interactions, we have developed a molecular mechanics force field for imatinib and four close analogues, which is consistent with the CHARMM force field for proteins and nucleic acids. Atomic charges and Lennard‐Jones parameters were derived from a supermolecule ab initio approach. We considered the ab initio energies and geometries of a probe water molecule interacting with imatinib fragments at 32 different positions. We considered both a neutral and a protonated imatinib. The final RMS deviation between the ab initio and force field energies, averaged over both forms, was 0.2 kcal/mol. The model also reproduces the ab initio geometry and flexibility of imatinib. To apply the force field to imatinib:Abl simulations, it is also necessary to determine the most likely imatinib protonation state when it binds to Abl. This was done using molecular dynamics free energy simulations, where imatinib is reversibly protonated during a series of MD simulations, both in solution and in complex with Abl. The simulations indicate that imatinib binds to Abl in its protonated, positively‐charged form. To help test the force field and the protonation prediction, we did MD free energy simulations that compare the Abl binding affinities of two imatinib analogs, obtaining good agreement with experiment. Finally, two new imatinib variants were considered, one of which is predicted to have improved Abl binding. This variant could be of interest as a potential drug. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

圆管流动水击压力波测量及水力计算

为探索水击现象的物理过程和机理,研制了自循环定常流动管路瞬态特性计算机控制试验装置,并利用该装置进行圆管流动水击压力波实验测量。用12只扩散硅压力传感器测定圆管流动水击压力波瞬态分布及最大、最小压力值,由试验数据拟合出水击波波形,揭示了水击压力波传播方式、特性及衰减规律。通过分析随机捕捉测量技术方法,理论上推断出测量数据达到可信精度。在归纳分析试验数据基础上,得出最大压力随关阀时间的关系曲线,对圆管流动直接水击等概念进行了探讨,用数值分析方法拟合出水击最大压力水力计算修正方程式。     

Formation Mechanism and Stability Study of Konjac Glucomannan Helical Structure

The formation mechanism and stability of konjac glucomannan (KGM) helical structure were investigated by molecular dynamic simulation and experimental method. The results indicate that the molecular conformation of KGM is a non-typical helical structure. In detail, helical structure of KGM is mainly sustained by acetyl group, whose size and stability are affected by the molecular polymerization degree of KGM. In vacuum among the non-bonding interactions, electrostatic force is the greatest factor affecting its helical structure, but in water solution, hydrogen bond affects the helical arrangement greatly. To our interest, temperature exhibits a reversible destroying effect to some extent; the helical structure will disappear completely and present a ruleless clew-like arrangement till 341 K. This work suggests that the method of combining molecular dynamic simulation and experiment tools can be effective in the study of KGM helical structure.     

A comprehensive Monte Carlo simulation of styrene atom transfer radical polymerization

<正>An optimized and high-performance Monte Carlo simulation is developed to take thorough account of four different cases of termination in styrene ATRP.According to the simulation results,the bimolecular termination rate constant sharply drops throughout the polymerization when either chain-length dependency of termination rate constant,gel effect,or both together is applied to the simulation.In addition,as expected,the initiator is quickly decomposed at the early stages of the polymerization.The concentration of the catalyst in lower oxidation state decreases at first and then plateaus at higher conversion;furthermore,the steady concentration of M_t~nY/L in the polymerization is the highest when the chain-length-dependent diffusion-controlled termination rate constant is employed in the simulation.The rates of deactivation and chain end degradation reactions are also smaller in this case.Therefore,the fraction of dormant chains is higher throughout the reaction and consequently the portion of dead polymers decreases.Besides,molecular weight increases linearly with conversion;however,when neither gel effect nor chain-length dependency of termination rate constant is considered,the molecular weight deviates from linearity at the end of the reaction.The peak of chain length distribution shifts toward higher molecular weight too during the reaction.Finally,the molecular weight distribution broadens at higher conversion;however, the chain length distribution of polymers produced under conditions of applying chain-length-dependent diffusion-controlled termination rate constant is narrower.     

空气污染组分H2O和CO2对乙烯燃烧性能的影响(II)——反应机理和动力学模拟

超燃冲压发动机在高空工作时, 以高温高速纯净空气作氧化剂使燃料燃烧. 但在地面实验中, 高温空气往往通过燃烧加热方式获得, 会使空气中含有H2O和CO2等污染组分. 本文用活塞流反应器进行动力学模拟, 研究在不同初温、压强和燃气比的条件下, H2O和CO2污染组分对乙烯燃烧的温度、压强和点火延迟时间等特性的影响. 模拟结果表明: 乙烯在含有H2O/CO2污染物的空气中燃烧, 相比纯净的空气而言, H2O对乙烯的点火有一定的促进作用, 而CO2有一定的抑制作用; 空气中含H2O和CO2污染物使乙烯燃烧的平衡温度和压强降低, 在污染物浓度相同时, CO2引起的下降幅度比H2O的大. 模拟结果能较好地解释现有的实验现象.     

海藻糖抑制淀粉质多肽42构象转变的分子动力学模拟

应用分子动力学模拟方法研究了海藻糖抑制淀粉质多肽42(Aβ42)构象转变的分子机理.结果表明,海藻糖溶液浓度对Aβ42构象转变具有非常重要的影响.在水和低浓度海藻糖溶液(0.18mol·L-1)中,Aβ42可由初始的α-螺旋结构转变成β-折叠的二级结构;但海藻糖浓度为0.37mol·L-1时即可有效抑制Aβ42的构象转变.这是因为海藻糖利用其优先排阻作用使水分子在多肽周围0.2nm内富集,而其自身却在距离多肽0.4nm的位置附近团聚.另外,海藻糖还可通过降低多肽间的疏水相互作用,减少多肽分子内远距离的接触,有效抑制多肽的疏水塌缩和构象转变.上述分子模拟的结果对于进一步合理设计阿尔茨海默病的高效抑制剂具有非常重要的理论指导意义.     

第一原理分子动力学研究类金刚石薄膜的结合强度与摩擦性能

金刚石(110)表面具有不同方向上抛光速率的强烈不对称的特征,用第一性原理全能量平面波赝势方法模拟研究了类金刚石薄膜表面的结合强度与摩擦性能,确定了相互作用模型以及排斥力作用范围,研究了范德华排斥力在摩擦表面上的分布,研究结果表明,摩擦表层感受到的力在〈001〉和〈110〉2个方向上表现明显不同,而且〈110〉方向上摩擦力一直高于〈001〉方向上的摩擦力.