Applying linear interaction energy method for binding affinity calculations of podophyllotoxin analogues with tubulin using continuum solvent model and prediction of cytotoxic activity

Podophyllotoxin and its analogues have important therapeutic value in the treatment of cancer, due to their ability to induce apoptosis in cancer cells in a proliferation-independent manner. These ligands bind to colchicine binding site of tubulin near the α- and β-tubulin interface and interfere with tubulin polymerization. The binding free energies of podophyllotoxin-based inhibitors of tubulin were computed using a linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model. A training set of 76 podophyllotoxin analogues was used to build a binding affinity model for estimating the free energy of binding for 36 inhibitors (test set) with diverse structural modifications. The average root mean square error (RMSE) between the experimental and predicted binding free energy values was 0.56 kcal/mol which is comparable to the level of accuracy achieved by the most accurate methods, such as free energy perturbation (FEP) or thermodynamic integration (TI). The squared correlation coefficient between experimental and SGB–LIE estimates for the free energy for the test set compounds is also significant (R² = 0.733). On the basis of the analysis of the binding energy, we propose that the three-dimensional conformation of the A, B, C and D rings is important for interaction with tubulin. On the basis of this insight, 12 analogues of varying ring modification were taken, tested with LIE methodology and then validated with their experimental potencies of tubulin polymerization inhibition. Low levels of RMSE for the majority of inhibitors establish the structure-based LIE method as an efficient tool for generating more potent and specific inhibitors of tubulin by testing rationally designed lead compounds based on podophyllotoxin derivatization.     

Applying linear interaction energy method for binding affinity calculations of podophyllotoxin analogues with tubulin using continuum solvent model and prediction of cytotoxic activity

Podophyllotoxin and its analogues have important therapeutic value in the treatment of cancer, due to their ability to induce apoptosis in cancer cells in a proliferation-independent manner. These ligands bind to colchicine binding site of tubulin near the α- and β-tubulin interface and interfere with tubulin polymerization. The binding free energies of podophyllotoxin-based inhibitors of tubulin were computed using a linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model. A training set of 76 podophyllotoxin analogues was used to build a binding affinity model for estimating the free energy of binding for 36 inhibitors (test set) with diverse structural modifications. The average root mean square error (RMSE) between the experimental and predicted binding free energy values was 0.56 kcal/mol which is comparable to the level of accuracy achieved by the most accurate methods, such as free energy perturbation (FEP) or thermodynamic integration (TI). The squared correlation coefficient between experimental and SGB–LIE estimates for the free energy for the test set compounds is also significant (R² = 0.733). On the basis of the analysis of the binding energy, we propose that the three-dimensional conformation of the A, B, C and D rings is important for interaction with tubulin. On the basis of this insight, 12 analogues of varying ring modification were taken, tested with LIE methodology and then validated with their experimental potencies of tubulin polymerization inhibition. Low levels of RMSE for the majority of inhibitors establish the structure-based LIE method as an efficient tool for generating more potent and specific inhibitors of tubulin by testing rationally designed lead compounds based on podophyllotoxin derivatization.     

A reduce package for determining lie symmetries of ordinary and partial differential equations

Title of program: LIE0,LIE1,LIE2,LIE3,LIE4 Catalogue number: AAZB Program obtainable form: CPC Program library, Queen's University in Belfast, N. Ireland (see application form in this issue) Computer: Siemens 7.760 Operating system: BS 2000 Programming language used: LISP High speed storage required: depends on the problem, minimum about 400 000 bytes No. of bits in a word: 32 Number of cards in combined program and test deck: 200     

Binding affinity models for Falcipain inhibition based on the Linear Interaction Energy method

The high rate of drug resistance as well as the complex biochemical process of the parasite reproduction cycle makes development of new drugs for malaria a very important but challenging task. Falcipain 2 (FL2) and Falcipain 3 (FL3) are the major cysteine protease enzymes that play a central role in providing essential amino acids for the parasite’s protein biosynthesis through the hemoglobin hydrolysis process. Selective inhibition of these enzymes is considered as a promising chemotherapeutic target. In the present investigation, the highly efficient linear interaction energy (LIE) method has been parameterized for binding affinity predictions and assessed with a set of 244 compounds for FL2 and FL3 inhibition. The results revealed that the van der Waals energy is very important for ligands binding to Falcipain proteins and that, overall, the electrostatic energy contribution is minor. The best models obtained for FL2 and FL3 give root mean square errors (RMSE) of 1.82 and 1.33 kcal/mol respectively, for the test set. In this study, we also investigate how the choice of initial protein-ligand confirmation (pose) impacts the overall quality of the LIE models. Moreover, the transferability of LIE parameters is further discussed.     

Recent conferences in Italy

Conclusions The conferences were very different in nature, each being valuable in its own way. The first brought together many people from all parts of the world making it possible to gain an overall view on the state of the art in the growing field of computational linguistics, and provided a forum for the interchange of ideas, and also enabled those who are new to such research to benefit from communication with those who are acknowledged leaders in the field. The LIE colloquium was more akin to a working group of experts who had been invited to participate in the LIE project to ensure the end product is of the highest possible standard by consultation and planning of a type that can only be achieved under such “interactive” conditions. Communication was two-way to the mutual benefit of all who attended.     

Linear interaction energy models for β-secretase (BACE) inhibitors: Role of van der Waals,electrostatic, and continuum-solvation terms

Computing the binding affinity of a protein–ligand complex is one of the most fundamental and difficult tasks in computer-aided drug design. Many approaches for computing binding affinities can be classified as linear interaction energy (LIE) models as they rely on some type of linear fit of computed interaction energies between ligand and protein. We have examined the computed interaction energies of a series of β-secretase (BACE) inhibitors in terms of van der Waals, coulombic, and continuum-solvation contributions to ligand binding. We have also systematically examined the effect of different protonation states of the protein and ligands. We find that the binding affinities are relatively insensitive to the protonation state of the protein when neutral ligands are considered. Inclusion of charged ligands leads to large deviations in the coulomb, solvation, and even van der Waals terms. The latter is due to increased repulsive van der Waals interactions in the complex due to the strong coulomb attraction found between oppositely charged functional groups in the protein and ligand. In general, we find that the best models are obtained when the protein is judiciously charged (e.g. Asp32⁻, Arg235⁺) and the potentially charged ligands are treated as neutral.     

Linear interaction energy models for beta-secretase (BACE) inhibitors: Role of van der Waals, electrostatic, and continuum-solvation terms

Computing the binding affinity of a protein–ligand complex is one of the most fundamental and difficult tasks in computer-aided drug design. Many approaches for computing binding affinities can be classified as linear interaction energy (LIE) models as they rely on some type of linear fit of computed interaction energies between ligand and protein. We have examined the computed interaction energies of a series of β-secretase (BACE) inhibitors in terms of van der Waals, coulombic, and continuum-solvation contributions to ligand binding. We have also systematically examined the effect of different protonation states of the protein and ligands. We find that the binding affinities are relatively insensitive to the protonation state of the protein when neutral ligands are considered. Inclusion of charged ligands leads to large deviations in the coulomb, solvation, and even van der Waals terms. The latter is due to increased repulsive van der Waals interactions in the complex due to the strong coulomb attraction found between oppositely charged functional groups in the protein and ligand. In general, we find that the best models are obtained when the protein is judiciously charged (e.g. Asp32⁻, Arg235⁺) and the potentially charged ligands are treated as neutral.     

Predicting proteinase specificities from free energy calculations

The role of the primary binding residue (P1) in complexes between three different subtilases (subtilisin Carlsberg, thermitase and proteinase K) and their canonical protein inhibitor eglin c have been studied by free energy calculations. Based on the crystal structures of eglin c in complex with subtilisin Carlsberg and thermitase, and a homology model of the eglin c-proteinase K complex, a total of 57 mutants have been constructed and docked into their host proteins. The binding free energy was then calculated using molecular dynamics (MD) simulations combined with the linear interaction energy (LIE) method for all complexes differing only in the nature of the amino acid at the P1 position. LIE calculations for 19 different complexes for each subtilase were thus carried out excluding proline. The effects of substitutions at the P1 position on the binding free energies are found to be very large, and positively charged residues (Arg, Lys and His) are particularly deleterious for all three enzymes. The charged variants of the acidic side chains are found to bind more favorably as compared to their protonated states in all three subtilases. Furthermore, hydrophobic amino acids are accommodated most favorably at the S1-site in all three enzymes. Comparison of the three series of binding free energies shows only minor differences in the 19 computed relative binding free energies among these subtilases. This is further reflected in the correlation coefficient between the 23 relative binding free energies obtained, including the possible protonation states of ionizable side chains, but excluding the P1 Pro, for subtilisin Carlsberg versus thermitase (0.95), subtilisin versus proteinase K (0.94) and thermitase versus proteinase K (0.96).     

The numerical integration of laminar boundary layer equations

Self-similar solutions of boundary layer equations obey non-linear differential equations, automorphic under certain continuous transformation groups. Changes of variables suggested by the theory of continuous LIE groups may reduce the problem to the integration of a first order non linear differential equation, followed by quadratures, thereby greatly simplifying computer integration.The famous Blasius equation, governing the asymptotic laminar boundary layer flow over a semi-infinite plate is presented as a typical example.     

A new level set method for inhomogeneous image segmentation

Intensity inhomogeneity often appears in medical images, such as X-ray tomography and magnetic resonance (MR) images, due to technical limitations or artifacts introduced by the object being imaged. It is difficult to segment such images by traditional level set based segmentation models. In this paper, we propose a new level set method integrating local and global intensity information adaptively to segment inhomogeneous images. The local image information is associated with the intensity difference between the average of local intensity distribution and the original image, which can significantly increase the contrast between foreground and background. Thus, the images with intensity inhomogeneity can be efficiently segmented. What is more, to avoid the re-initialization of the level set function and shorten the computational time, a simple and fast level set evolution formulation is used in the numerical implementation. Experimental results on synthetic images as well as real medical images are shown in the paper to demonstrate the efficiency and robustness of the proposed method.     

A comparative study of some computer algebra packages which determine the Lie point symmetries of differential equations

The study seeks to determine which of five computer algebra packages is best at finding the Lie point symmetries of systems of partial differential equations with minimal user intervention. The chosen packages are LIEPDE and DIMSYM for REDUCE, LIE and BIGLIE for MUMATH, DESOLV for MAPLE, and MATHLIE for MATHEMATICA. A series of systems of partial differential equations are used in the study. The paper concludes that while all of the computer packages are useful, DESOLV appears to be the most successful system at determining the complete set of Lie point symmetries of systems of partial differential equations.     

聚焦超声在脱气水声场中的多泡分布与声致发光研究

为明确多泡空化在高强度聚焦超声（High intensity focused ultrasound,HIFU）治疗中焦前区、焦后区的副作用,进一步优化HIFU治疗,本文在不同声强下利用高速摄像系统与数字相机拍摄聚焦超声在脱气水声场中的多泡及多泡声致发光（Multi-bubble sonoluminescence,MBSL）的空间分布,通过被动空化检测（Passive cavitation detection,PCD）技术和光电倍增管（Photomultiplier tube,PMT）系统检测多泡空化特征及声场整体发光强度。研究表明：当声强较低时（如3 047 W/cm²）,气泡以驻波场模式分布;随着声强的提高,焦点处出现向焦后方生长的气泡群,3~6 MHz宽带噪声增幅明显,同时MBSL最先出现在焦前区,并向换能器表面扩大,声场整体发光强度与声强成正比;当声强足够高时（如21 328 W/cm²）,焦点处空化泡群剧烈坍缩的同时可见椭球形光斑,嘶嘶声不断,气泡的聚集大大降低了声场的相对发光强度。     

Evaluation of draught in the workplace

During 826, 1-h sessions 107 participants (33 women, 74 men, 18-51 years of age) were exposed to defined draughts where air velocity (0.1 < or = V(a) < or = 0.4 m s(-1)), turbulence intensity (< 30, approximately equal to 50, > 70%), draught direction (horizontal, vertical, diagonal), air temperature (11 < or = t(a) < or = 23 degrees C), and metabolic rate ( approximately equal to 60< or = M < or = 156 W m(-2)) were varied but kept constant during single sessions. Perception and evaluation (annoyance due to draught and local cold) were registered using a list of prescribed body parts. Annoyance due to draught increased with the increase in mean air velocity and in turbulence intensity, as well as with the decrease in air temperature and in metabolic rate. The direction of air flow had no influence. As these responses were neither sufficiently predicted by the draught-rating model proposed in ISO 7730 (1994), nor by its extension developed by Toftum (1994a), the latter was modified according to the data registered in this paper. Using the modified model the accordingly predicted percentage of people annoyed by draught agreed highly with the percentage actually observed (r=0.726, p<0.001). As the resulting model covers larger ranges of air temperature and metabolic rate it is suggested that it should substitute the model proposed in ISO 7730 [1994].     

基于多尺度梯度域引导滤波的低照度图像增强算法

针对低照度彩色图像整体亮度较低，增强图像中颜色易失真，部分图像细节淹没在较低灰度值像素中等问题，提出一种改进的低照度图像增强算法。首先，把待处理图像转换到色调、饱和度、亮度（HSI）颜色空间，对亮度分量进行非线性全局亮度校正；然后，提出多尺度梯度域引导滤波的亮度增强模型，利用该模型对校正后的亮度分量进行增强，接着对增强后的亮度分量进一步实施避免颜色失真的亮度校正；最后，将图像再转换回红绿蓝（RGB）颜色空间。实验结果表明，增强后的图像亮度平均提高90.0%以上，清晰度平均提高123.8%以上，这主要得益于多尺度梯度域引导滤波具有更好的亮度平滑和增强能力；同时由于减小了颜色失真，使增强图像的细节表现能力平均提高18.2%以上；由于采用了多尺度梯度域引导滤波的亮度增强模型与直方图自适应的亮度校正算法，使提出的低照度图像增强算法适宜应用于夜间等弱光源条件下的彩色图像增强。     

Evaluation of draught in the workplace

During 826, 1-h sessions 107 participants (33 women, 74 men, 18-51 years of age) were exposed to defined draughts where air velocity (0.1 ≤ V a ≤ 0.4 m s -1), turbulence intensity (<30, ≈ 50, >70%), draught direction (horizontal, vertical, diagonal), air temperature (11 ≤ t a ≤ 23°C), and metabolic rate (≈ 60 ≤ M ≤ 156 W m -2) were varied but kept constant during single sessions. Perception and evaluation (annoyance due to draught and local cold) were registered using a list of prescribed body parts. Annoyance due to draught increased with the increase in mean air velocity and in turbulence intensity, as well as with the decrease in air temperature and in metabolic rate. The direction of air flow had no influence. As these responses were neither sufficiently predicted by the draught-rating model proposed in ISO 7730 (1994), nor by its extension developed by Toftum (1994a), the latter was modified according to the data registered in this paper. Using the modified model the accordingly predicted percentage of people annoyed by draught agreed highly with the percentage actually observed (r =0.726, p <0.001). As the resulting model covers larger ranges of air temperature and metabolic rate it is suggested that it should substitute the model proposed in ISO 7730 [1994].     

Electrokinetic characterization of individual nanoparticles in nanofluidic channels

We electrokinetically characterize properties of single 42-nm polystyrene nanoparticles (NP) in nanofluidic channels imaged with frustrated total internal reflection fluorescence microscopy (fTIRFM). Specifically, we demonstrate fTIRFM of individual NPs in nanofluidic channels shallower than the evanescent field and use the resultant illumination field to gain insight into the behavior and electrokinetic properties of individual NP transport in channels. We find that the electrophoretic mobility of nanoparticles in 100-nm channels is lower than in larger channels or in bulk, presumably due to hindrance effects. Furthermore, we notice a non-intuitive increase in mobility with buffer concentration, which we attribute to electric double layer interactions. Finally, since the evanescent field intensity decreases with distance from the channel wall, we use the measured fluorescence intensity to report probable transverse distributions of free-solution 42-nm polystyrene fluorescent particles. Our method promises to be useful for characterizing nanoscale molecules for many applications in drug discovery, bioanalytics, nanoparticle synthesis, viral targeting, and the basic science of understanding nanoparticle behavior.     

基于可变步长PCNN赋时矩阵高斯噪声滤波

提出了一种用脉冲耦合神经网络(pulse-coupled neural network,PCNN)赋时矩阵定位噪声、分类滤波并能自适应调整灰度补偿步长的高斯噪声滤波方法。使用PCNN求得含噪图像的赋时矩阵,再在滤波窗口中根据目标像素与周围像素的点火时刻关系确定噪声点,对噪声点分4类滤波:增加、减少可变灰度步长,维纳滤波和中值滤波,最后对图像维纳滤波平滑小噪声点。实验结果表明,该算法能有效去除噪声且较好保持图像的边缘细节,与同类高斯滤波方法进行峰值信噪比、信噪比改善因子比较,验证了算法的有效性。     

Temperature-dependent remote control of polarization and coherence intensity with sender’s pure initial state

We study the remote creation of the polarization and intensity of the first-order coherence (or coherence intensity) in long spin-1/2 chains with one-qubit sender and receiver. Therewith we use a physically motivated initial condition with the pure state of the sender and the thermodynamical equilibrium state of the other nodes. The main part of the creatable region is a one-to-one map of the initial state (control) parameters, except the small subregion twice covered by the control parameters, which appears owing to the chosen initial state. The polarization and coherence intensity behave differently in the state creation process. In particular, the coherence intensity cannot reach any significant value unless the polarization is large in long chains (unlike the short ones), but the opposite is not true. The coherence intensity vanishes with an increase in the chain length, while the polarization (by absolute value) is not sensitive to this parameter. We represent several characteristics of the creatable polarization and coherence intensity and describe their relation to the parameters of the initial state. The link to the eigenvalue–eigenvector parametrization of the receiver’s state space is given.     

Analysis of the performance of subcarrier multiplexed (SCM) optical systems

In addition to the distortion effect due to the quadratic phase response of single-mode optical fiber, other impairments affect subcarrier multiplexed (SCM) optical transmission systems when using either semiconductor lasers or intensity external modulators at the transmitter in the case of hybrid AM/QAM channeling. In the first case several effects are considered, which give rise to different distortion phenomena: intrinsic “dynamic” distortions due to interaction of photons and electrons in a semiconductor laser, clipping impulsive noise, AM-FM conversion effect due to the joint action of semiconductor laser static and dynamic chirping and fiber chromatic dispersion, nonlinear distortions due to the Kerr effect, interferometric noise due to the joint action of semiconductor laser chirping and optical fibre multiple reflections. In the case of an external intensity modulator, the distortion noise due to its intrinsic nonlinear response is analyzed. The analysis provides useful information about the design and the performance evaluation of SCM based optical access networks.