Maximum-entropy decomposition of fluorescence correlation spectroscopy data: application to liposome–human serum albumin association

Fluorescence correlation spectroscopy was used to measure the diffusion behavior of a mixture of DMPC or DMPC/DMPG liposomes with human serum albumin (HSA) and mesoporphyrin (MP), which was used as the fluorescent label for liposomes and HSA as well. For decomposing the fluorescence intensity autocorrelation function (ACF) into components corresponding to a liposome population, HSA and MP, we used a maximum entropy procedure that computes a distribution of diffusion times consistent with the ACF data. We found that a simple parametric non-linear fit with a discrete set of decay components did not converge to a stable parameter set. The distribution calculated with the maximum entropy method was stable and the average size of the particles calculated from the effective diffusion time was in good agreement with the data determined using the discrete-component fit.     

基于信息论k—modes聚类法的基因表达数据分析

k-均值聚类算法是一种广泛应用于基因表达数据聚类分析中的迭代变换算法,它通常用距离法来表示基因间的关系,但不能有效的反应基因间的相互依赖的关系。为此,提出基于信息论的k-modes聚类算法,克服了以上缺点。另外,还引入了伪F统计量,一方面,可以对空间中有部分重叠的点进行有效的分类;另一方面,可以给出最佳聚类数目,从而弥补了k-modes聚类法的不足。使其成为一种非常有效的算法,从而达到较优的聚类效果。     

细胞寒害的热力学熵理论(Ⅱ)──超熵产生作为寒害稳定性判据的理论研究

本文从物质和能量交换的角度,运用非平衡态热力学超熵产生理论,分析了寒害定态的稳定性,并建立了超熵产生判据．理论分析所得的结论与实验结果基本相符．     

OPUS-Dom: Applying the Folding-Based Method VECFOLD to Determine Protein Domain Boundaries

In this article, we present a de novo method for predicting protein domain boundaries, called OPUS-Dom. The core of the method is a novel coarse-grained folding method, VECFOLD, which constructs low-resolution structural models from a target sequence by folding a chain of vectors representing the predicted secondary-structure elements. OPUS-Dom generates a large ensemble of folded structure decoys by VECFOLD and labels the domain boundaries of each decoy by a domain parsing algorithm. Consensus domain boundaries are then derived from the statistical distribution of the putative boundaries and three empirical sequence-based domain profiles. OPUS-Dom generally outperformed several state-of-the-art domain prediction algorithms over various benchmark protein sets. Even though each VECFOLD-generated structure contains large errors, collectively these structures provide a more robust delineation of domain boundaries. The success of OPUS-Dom suggests that the arrangement of protein domains is more a consequence of limited coordination patterns per domain arising from tertiary packing of secondary-structure segments, rather than sequence-specific constraints.     

Evidence for an internal entropy contribution to phosphoryl transfer: a study of domain closure, backbone flexibility, and the catalytic cycle of cAMP-dependent protein kinase.

While there is no question that ligands can induce large-scale domain movements that narrow (close) the active-site cleft of the catalytic (C) subunit of cAMP-dependent protein kinase (cAPK), the results from small-angle X-ray scattering, protein footprinting, and thermostability studies are inconsistent with regard to which ligands induce these movements. This inconsistency suggests a greater complexity of cAPK conformational dynamics than is generally recognized. As an initial step to study this issue in relation to the catalysis, a new method to measure cAPK domain closure was developed, and the state of domain closure and the local segmental flexibility at major steps of the cAPK catalytic cycle were examined with site-directed labeling and fluorescence spectroscopy. To achieve this, a C subunit mutant (F239C/C199A) was engineered that allowed for fluorescein 5-maleimide (donor) conjugation of F239C in the large lobe and tetramethylrhodamine (acceptor) conjugation of C343 in the small lobe. Domain closure was assessed as an increase in the efficiency of energy transfer between donor and acceptor. The anisotropy decay of fluoroscein 5-maleimide, conjugated to a site of cysteine substitution (K81C) in the small lobe of the C subunit was used to assess the local backbone flexibility around the B helix. The effects of substrate/pseudosubstrate (ATP and PKI(5-24)), a fragment of protein kinase inhibitor) and products (ADP and phosphorylated PKS) on domain closure and B helix flexibility were measured. The results show that domain closure is not tightly coupled to the flexibility around K81C. Moreover, although substrates/pseudosubstrate and products independently close the active-site cleft, only the substrates substantially decreased the backbone flexibility around the B helix. Because this order-to-disorder transition coincides with the phosphoryl transfer transition, the results suggest the existence of an internal entropy contribution to catalysis.     

Backbone entropy of loops as a measure of their flexibility: Application to a Ras protein simulated by molecular dynamics

The flexibility of surface loops plays an important role in protein–protein and protein–peptide recognition; it is commonly studied by Molecular Dynamics or Monte Carlo simulations. We propose to measure the relative backbone flexibility of loops by the difference in their backbone conformational entropies, which are calculated here with the local states (LS) method of Meirovitch. Thus, one can compare the entropies of loops of the same protein or, under certain simulation conditions, of different proteins. These loops should be equal in size but can differ in their sequence of amino acids residues. This methodology is applied successfully to three segments of 10 residues of a Ras protein simulated by the stochastic boundary molecular dynamics procedure. For the first time estimates of backbone entropy differences are obtained, and their correlation with B factors is pointed out; for example, the segments which consist of residues 60–65 and 112–117 have average B factors of 67 and 18 Ų, respectively, and entropy difference T ΔS = 5.4 ± 0.1 kcal/mol at T = 300 K. In a large number of recent publications the entropy due to the fast motions (on the ps-ns time scale) of N–H and C–H vectors has been obtained from their order parameter, measured in nuclear magnetic resonance spin relaxation experiments. This enables one to estimate differences in the entropy of protein segments due to folding–unfolding transitions, for example. However, the vectors are assumed to be independent, and the effect of the neglected correlations is unknown; our method is expected to become an important tool for assessing this approximation. The present calculations, obtained with the LS method, suggest that the errors involved in experimental entropy differences might not be large; however, this should be verified in each case. Potential applications of entropy calculations to rational drug design are discussed. Proteins 29:127–140, 1997. © 1997 Wiley-Liss, Inc.     

中国柯属5种资源植物潜在地理分布及其对气候变化的响应

利用最大墒模型和地理信息系统软件对柯属（Lithocarpus）5种资源植物在我国的适宜分布区进行了定量预测,并对未来不同气候情景下其分布区的变化进行了分析。结果显示：木姜叶柯（L.litseifolius（Hance）Chun.）在我国秦岭淮河以南广泛分布,短尾柯（L.brevicaudatus（Skan）Hay.）主要分布在我国亚热带中东部区域;木姜叶柯在未来气候（2061-2080年）RCP2.6、RCP8.5两种情景下适生区面积分别减少了5.1%和3.0%,而短尾柯却分别增加了0.5%和1.5%。白柯（L.dealbatus（Hook.f.et Thoms.ex DC.）Rehd.）适宜区主要分布在云南北部、四川南部,烟斗柯（L.corneus（Lour.）Rehd.）主要分布在两广省份的南亚热带地区。白柯和烟斗柯在RCP2.6情景下适生区面积分别减少了12.1%和17.8%,在RCP8.5情景下分别减少了3.5%和15.9%,这两个种的适宜区面积减少较多。厚斗柯（L.elizabethae（Tutch.）Rehd.）主要分布于广西,在两种情景下适宜区面积分别增加了7.3%和6.3%。研究结果表明,由于分布区存在差异,同属不同物种的未来分布对气候变化的响应不同。     

A statistical rescoring scheme for protein-ligand docking: Consideration of entropic effect

Computational prediction of protein-ligand binding modes provides useful information on the relationship between structure and activity needed for drug design. A statistical rescoring method that incorporates entropic effect is proposed to improve the accuracy of binding mode prediction. A probability function for two sampled conformations to belong to the same broad basin in the potential energy surface is introduced to estimate the contribution of the state represented by a sampled conformation to the configurational integral. The rescoring function is reduced to the colony energy introduced by Xiang et al. (Proc Natl Acad Sci USA 2002;99:7432-7437) when a particular functional form for the probability function is used. The scheme is applied to rescore protein-ligand complex conformations generated by AutoDock. It is demonstrated that this simple rescoring improves prediction accuracy substantially when tested on 163 protein-ligand complexes with known experimental structures. For example, the percentage of complexes for which predicted ligand conformations are within 1 A root-mean-square deviation from the native conformations is doubled from about 20% to more than 40%. Rescoring with 11 different scoring functions including AutoDock scoring functions were also tested using the ensemble of conformations generated by Wang et al. (J Med Chem 2003;46:2287-2303). Comparison with other methods that use clustering and estimation of conformational entropy is provided. Examination of the docked poses reveals that the rescoring corrects the predictions in which ligands are tightly fit into the binding pockets and have low energies, but have too little room for conformational freedom and thus have low entropy.