Modified AutoDock for accurate docking of protein kinase inhibitors

Protein kinases are an important class of enzymes controlling virtually all cellular signaling pathways. Consequently, selective inhibitors of protein kinases have attracted significant interest as potential new drugs for many diseases. Computational methods, including molecular docking, have increasingly been used in the inhibitor design process [1]. We have considered several docking packages in order to strengthen our kinase inhibitor work with computational capabilities. In our experience, AutoDock offered a reasonable combination of accuracy and speed, as opposed to methods that specialize either in fast database searches or detailed and computationally intensive calculations.However, AutoDock did not perform well in cases where extensive hydrophobic contacts were involved, such as docking of SB203580 to its target protein kinase p38. Another shortcoming was a hydrogen bonding energy function, which underestimated the attraction component and, thus, did not allow for sufficiently accurate modeling of the key hydrogen bonds in the kinase-inhibitor complexes.We have modified the parameter set used to model hydrogen bonds, which increased the accuracy of AutoDock and appeared to be generally applicable to many kinase-inhibitor pairs without customization. Binding to largely hydrophobic sites, such as the active site of p38, was significantly improved by introducing a correction factor selectively affecting only carbon and hydrogen energy grids, thus, providing an effective, although approximate, treatment of solvation.     

超支化聚合反应的多尺度模拟

超支化聚合物具有与树枝状大分子相似的物理和化学性质,其具有合成简单、分子量分布宽等突出特点,超支化聚合物分子的结构形成取决于聚合反应过程,本文介绍了超支化聚合反应模拟研究的最新进展.首先介绍了八位置键涨落粗粒化格子模型在超支化聚合反应模拟中的应用,该方法考虑了聚合物分子空间位阻效应、分子内成环和反应点活性等影响因素,从而可以模拟不同类型的超支化聚合反应;为了定量描述单体和聚合物分子结构,研究者进一步发展了杂化多尺度超支化聚合反应模拟方法,该方法通过玻尔兹曼反演迭代方法获取单体和聚合物特异性粗粒化力场,然后通过粗粒化分子动力学方法结合反应性Monte Carlo方法对特异性超支化聚合反应进行定量模拟.多尺度聚合反应模拟不仅可以精确计算超支化聚合物分子量、多分散性指数和支化度等一般性聚合物参数,还可以获取分子成环率、超支化大分子构象等重要分子结构信息,在超支化聚合反应基础研究与预测方面具有重要应用价值.     

脱乙酰基对天然魔芋葡甘聚糖分子形貌的影响

通过原子力显微镜直接观察魔芋葡甘聚糖（KGM）分子的三维结构形貌,KGM水溶液铺展在经Ca^2 处理的云母片上,干燥固定后,可获得稳定,重复的图像,实验结果表明,稀溶液中KGM分子具有伸展的螺旋链状结构,单股的长度达200－400nm,厚度为1．0nm,宽度为35．0－35．2nm,脱乙酰后分子链卷曲成直径约40－50nm,厚3．5－5．0nm的弹性圆台状。     

Flexible matching of test ligands to a 3D pharmacophore using a molecular superposition force field: Comparison of predicted and experimental conformations of inhibitors of three enzymes

Summary A computer procedure TFIT, which uses a molecular superposition force field to flexibly match test compounds to a 3D pharmacophore, was evaluated to find out whether it could reliably predict the bioactive conformations of flexible ligands. The program superposition force field optimizes the overlap of those atoms of the test ligand and template that are of similar chemical type, by applying an attractive force between atoms of the test ligand and template which are close together and of similar type (hydrogen bonding, charge, hydrophobicity). A procedure involving Monte Carlo torsion perturbations, followed by torsional energy minimization, is used to find conformations of the test ligand which cominimize the internal energy of the ligand and the superposition energy of ligand and template. The procedure was tested by applying it to a series of flexible ligands for which the bioactive conformation was known experimentally. The 15 molecules tested were inhibitors of thermolysin, HIV-1 protease or endothiapepsin for which X-ray structures of the bioactive conformation were available. For each enzyme, one of the molecules served as a template and the others, after being conformationally randomized, were fitted. The fitted conformation was then compared to the known binding geometry. The matching procedure was successful in predicting the bioactive conformations of many of the structures tested. Significant deviation from experimental results was found only for parts of molecules where it was readily apparent that the template did not contain sufficient information to accurately determine the bioactive conformation.     

Surface forces in foam films from ABA block copolymer: a dynamic method study

The thinning of foam films from aqueous solutions of an ABA triblock copolymer of polyethylene oxide and polypropylene oxide (average molecular weight 14,000 g/mol) is studied experimentally. The dependence of the surface forces on film thickness is obtained by the dynamic method of Scheludko and Exerowa.The total surface force measured in foam films (radius 60–70 m) from 10^–5 M (0.014 wt%) polymer solution with 0.1 M NaCl is positive at thicknesses from about 800 down to 460 . The electrostatic repulsion is negligible while the contribution of van der Waals attraction is small (within 15%). Therefore a positive surface force component predominates. Most probably it arises from steric interactions between the hydrophilic polyethylene oxide tails of the polymer. The dynamic method appears to be a suitable technique for exploring the stabilization of foam films from ABA copolymers.     

Electron density distribution in potassium bis -(carbonato)cuprate(II)

The electron density distribution in potassiumbis-(carbonato)cuprate(II) has been analyzed using x-ray diffraction data from an earlier structure determination. While the copper-ligand geometry is close to square planar the deformation density near the metal is strongly asymmetric. There are local maxima near the copper atom along the line of the Cu-K vectors. These resemble features found in corresponding regions in normal length metal-metal bonds. The observation is consistent with the long range nature of the Coulomb potential associated with the potassium ion.     

Heterogeneous/homogeneous and inclined magnetic aspect of infinite shear rate viscosity model of Carreau fluid with nanoscale heat transport

The study of the inclined flow along with the heterogeneous/homogeneous reactions in the fluid has been widely used in many industrial and engineering applications, such as petrochemical, pharmaceutical, materials science, heat exchanger design, fluid flow through porous media, etc. The purpose of this study is to present an infinite shear rate viscosity model using the inclined Carreau fluid with nanoscale heat transport. The model considers the effect of inclined angle on the fluid’s viscosity and the transfer of heat at the nanoscale. The result shows that the viscosity of the fluid decreases by increasing the inclination angle and the coefficient of heat transfer also increases with the inclination. The model can be used to predict the viscosity and heat transfer fluid’s behavior in the inclined systems that is widely used in the industrial and engineering applications. The results provide a better understanding of the inclined flow behavior of fluids and the heat transfer at the nanoscale, which can be useful in heat exchanger design, fluid flow through porous media, etc. Greater Infinite shear rate viscosity parameter gives the higher magnitude of Carreau fluid velocity. Moreover, inclined magnetic field reduces the velocity due to Lorentz force. Two numerical schemes are used to solve the model, BVP4C and Shooting.     

Hydration forces between bilayers in the presence of dissolved or surface-linked sugars

We analyse the experimental evidence of the hydration force near phospholipid bilayers when the “solvent” is a solution of carbohydrates. Two cases must be clearly distinguished: when sugar is dissolved, depletion causes a supplementary attractive force, while in the case of sugar linked to the lipid the contact pressure increases by orders of magnitude. Attractive interaction inferred between bilayers is sometimes derived from indirect evidence, i.e. scattering, attraction between layers adsorbed, shape of phase boundary limits, and without the simultaneous determination of the osmotic compressibility. Generally, water molecules in the first hydration shell of sugar compete with water molecules bound (by more than one kT in free energy) to lipid head-groups. A general result is that the decay length of any repulsive effect remains close to 0.2 nm, even in concentrated sugar solutions. A tentative general explanation of this experimental fact is given together with consequences, such as the possibility of several types of critical points appearing in bilayer stacks. Decay length as well as effective contact pressure is considered with respect to carbohydrate activity.