别构酶活性调节的异位效应模型

考虑调节剂结合别构酶的异位效应,讨论了与别构部位结合的活性剂分子和抑制剂分子对别要酶和底物结合过程的影响以及它们对协同性效应和抗协同性效应的影响。     

别构酶ATCase与底物分子协同结合过程的构象变化特性

利用可描述协同结合特性的动力学方法,得到了反映单个别构酶ATCase分子的结合分数与底物浓度之间的关系式.表明在确定的底物浓度条件下,单个别构酶ATCase分子处于确定的构象态,随着底物浓度的增加,别构酶ATCase分子将经历一系列中间态达到饱和构象态,S型结合分数曲线实际上显示了单个别构酶ATCase分子与底物分子的协同结合特性.利用所得模型分析了调节物分子对底物协同结合过程的影响,合理解释了结合分数曲线随调节物浓度变化而发生改变的实验结果,与别构酶ATCase分子具有的结构及所产生的生物学功能是自给的.     

λ噬菌体调节蛋白与操纵基因相互作用的研究

根据λ噬菌体调节蛋白和特异的ＤＮＡ部位的相互作用提出一种线笥三位点的结合模型，从理论上解释了调节蛋白结合左右操纵基因的协同性，得出耦合自由能的分配。     

杂种优势的一种可能的分子机理——杂合酶的协同效应

根据酶的结构与催化功能关系原理，提出了杂种优势的一种分子机理的假设，即杂合酶的协同效应，显性互补和异质等位基因互补是其中两个特例。应用杂合酶的正负协同效应能够很好地解释杂种优势的正负性和强弱性。杂合酶的特性与杂种优势的许多性质是一致的。杂合酶的活性多态性得到了同工酶的验证，其中的杂合酶活性强度与杂种优势有很强的正相关。从多聚酶的亚基间相互作用所产生的构象变化的传递形成的催化反应的协同性，讨论了杂合     

基于双惩罚分位回归的面板数据模型理论与实证研究

固定效应和随机效应同时选择是面板数据模型研究中的重要问题之一。本文通过分别对固定效应和随机效应引入条件Laplace先验,提出了一种新的贝叶斯双惩罚分位回归法。该方法不仅能对模型中重要解释变量进行自动选择,而且充分考虑到个体随机波动对解释变量系数估计带来的偏差。通过对方差分量的惩罚压缩,减少了模型中未知参数的个数,提高了模型自由度。Monte Carlo模拟及实证分析显示,所提出的方法不仅能准确估计出固定效应系数,而且能精确地捕捉到个体随机效应的波动。     

二氧化锡薄膜的气敏光学作用机理研究

报导了ＳｎＯ２薄膜及其掺杂膜片在乙醇中的气敏光学效应与透射光谱特性；提出了一种新的理论模型来解释ＳｎＯ２薄膜的气敏光学效应的作用机理，并与实验结果一致，从而证明了该模型的正确性。     

一个“J”曲线动力学模型

简要介绍了社会经济系统中存在的“J”效应现象以及一些相关工作,并用系统动力学方法给出了一个“J”效应模型,提供一种对“J”效应形成机制的解释思路.     

Gpc径向尺度以上哥白尼原理的验证

哥白尼原理是现代宇宙学的基石之一.但是,Gpc径向尺度以上的哥白尼原理几乎没有得到确证.如果该类哥白尼原理遭到破坏,就会产生一阶各向异性运动学SZ（Sunyaev Zel＇dovich）效应.我们证明,如果这种破坏达到能够取代暗能量解释宇宙＂加速＂膨胀的程度,产生的运动学SZ效应功率谱将远远超出ACT/SPT实验的上限.该检验排除了空洞模型解释宇宙＂加速＂膨胀的可能性,证实了Gpc径向尺度以上的哥白尼原理,弥补了标准宇宙学中的一个漏洞.     

电热耦合效应的金属单点接触结构的无源互调研究

针对现有无源互调(PIM)模型不能准确解释互调机理并描述测试规律的问题,提出了一种基于电热耦合效应的PIM产生机理和模型,并利用金属单点接触结构进行了实验验证。首先,提出了一种基于缝隙波导近场耦合的PIM测试方法,该方法使待测结构与测试工装分离,克服了传统PIM实验研究针对整体微波部件进行测试分析的限制,能够实现单个点接触结构的PIM效应的研究;然后,对铝接触在不同状态下的表面成分和电接触特性进行研究,结果表明,金属表面存在的氧化层和沾污物是引起其接触结PIM产生和劣化的根本原因,微波辐照时电热耦合效应影响接触结的阻抗;最后,通过实验获取了铝、紫铜和黄铜等材料组成的单点接触结构的PIM,提出了基于电热耦合效应的PIM产生机理和模型。实验和理论结果表明,相对于传统的数学经验模型或多项式数学拟合,结合电热耦合的接触非线性模型,从物理底层出发,对PIM的产生根源和机理给出了明确解释,能够更加准确地计算和预测PIM。     

植物基因工程中的转基因沉默机制

植物转基因沉默可以发生在染色体DNA、转录和转录后三种不同的层次上,转录水平基因沉默机制涉及DNA甲基化、位置效应、重复序列、同源序列等作用。转录后水平基因沉默机制常用RNA域值模型、异常RNA模型、双链RNA模型、未成熟翻译终止模型等解释。目前没有一种通用的模型可以解释所有的转基因沉默现象,但不同模型从不同方面解释了转基因机制的某些方面。     

Exploitation of structural and regulatory diversity in glutamate racemases

Glutamate racemase is an enzyme essential to the bacterial cell wall biosynthesis pathway, and has therefore been considered as a target for antibacterial drug discovery. We characterized the glutamate racemases of several pathogenic bacteria using structural and biochemical approaches. Here we describe three distinct mechanisms of regulation for the family of glutamate racemases: allosteric activation by metabolic precursors, kinetic regulation through substrate inhibition, and D-glutamate recycling using a d-amino acid transaminase. In a search for selective inhibitors, we identified a series of uncompetitive inhibitors specifically targeting Helicobacter pylori glutamate racemase that bind to a cryptic allosteric site, and used these inhibitors to probe the mechanistic and dynamic features of the enzyme. These structural, kinetic and mutational studies provide insight into the physiological regulation of these essential enzymes and provide a basis for designing narrow-spectrum antimicrobial agents.     

HIV-1 蛋白酶异位抑制剂体系的长时间分子动力学模拟

采用新开发的ff12SB力场在NVIDIA CUDA GPU上对HIV-1蛋白酶的活性位抑制剂体系和异位抑制剂体系分别进行了100 ns的长时间分子动力学模拟,并用MM-PB/GBSA方法计算了活性位点抑制剂TL-3与HIV-1蛋白酶的结合自由能。异位抑制剂体系中分子片段2-甲基环己醇结合在Exo位,有利于抑制剂被束缚在活性位点附近。异位抑制剂体系中抑制剂TL-3与蛋白酶的结合自由能为-85.78 kcal/mol,活性位抑制剂体系中为-79.45 kcal/mol。这些结果有助于深入了解HIV-1 PR的动力学过程,为设计新型强效抑制剂提供了新见解。     

Regulation of carbamoyl phosphate synthetase by MAP kinase

The de novo synthesis of pyrimidine nucleotides is required for mammalian cells to proliferate. The rate-limiting step in this pathway is catalysed by carbamoyl phosphate synthetase (CPS II), part of the multifunctional enzyme CAD. Here we describe the regulation of CAD by the mitogen-activated protein (MAP) kinase cascade. When phosphorylated by MAP kinase in vitro or activated by epidermal growth factor in vivo, CAD lost its feedback inhibition (which is dependent on uridine triphosphate) and became more sensitive to activation (which depends upon phosphoribosyl pyrophosphate). Both these allosteric regulatory changes favour biosynthesis of pyrimidines for growth. They were accompanied by increased epidermal growth factor-dependent phosphorylation of CAD in vivo and were prevented by inhibition of MAP kinase. Mutation of a consensus MAP kinase phosphorylation site abolished the changes in CAD allosteric regulation that were stimulated by growth factors. Finally, consistent with an effect of MAP kinase signalling on CPS II activity, epidermal growth factor increased cellular uridine triphosphate and this increase was reversed by inhibition of MAP kinase. Hence these studies may indicate a direct link between activation of the MAP kinase cascade and de novo biosynthesis of pyrimidine nucleotides.     

艾滋病毒蛋白酶异位抑制剂体系的分子动力学研究

对艾滋病毒蛋白酶异位抑制剂体系和活性位抑制剂体系进行8 ns的分子动力学模拟,用MM-PBSA方法分别计算了抑制剂与蛋白酶的结合自由能。异位抑制剂体系中抑制剂与蛋白酶的结合自由能为-90.30 kcal/mol,活性位抑制剂体系中为-59.58 kcal/mol。在异位抑制剂体系中分子片段4DX卡在蛋白酶的exo位,使蛋白酶活性位点附近残基的活动范围减小,有利于抑制剂被束缚在活性位点附近。异位抑制剂使体系刚性更强,更稳定,抑制剂与蛋白酶的结合更为牢固。     

Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion

Neurotransmitter release is triggered by an increase in the cytosolic Ca2+ concentration ([Ca2+]i), but it is unknown whether the Ca2+-sensitivity of vesicle fusion is modulated during synaptic plasticity. We investigated whether the potentiation of neurotransmitter release by phorbol esters, which target presynaptic protein kinase C (PKC)/munc-13 signalling cascades, exerts a direct effect on the Ca2+-sensitivity of vesicle fusion. Using direct presynaptic Ca2+-manipulation and Ca2+ uncaging at a giant presynaptic terminal, the calyx of Held, we show that phorbol esters potentiate transmitter release by increasing the apparent Ca2+-sensitivity of vesicle fusion. Phorbol esters potentiate Ca2+-evoked release as well as the spontaneous release rate. We explain both effects by an increased fusion 'willingness' in a new allosteric model of Ca2+-activation of vesicle fusion. In agreement with an allosteric mechanism, we observe that the classically high Ca2+ cooperativity in triggering vesicle fusion (approximately 4) is gradually reduced below 3 microM [Ca2+]i, reaching a value of <1 at basal [Ca2+]i. Our data indicate that spontaneous transmitter release close to resting [Ca2+]i is a consequence of an intrinsic property of the molecular machinery that mediates synaptic vesicle fusion.     

The allosteric transition of glycogen phosphorylase

The crystal structure of R-state glycogen phosphorylase b has been determined at 2.9 A resolution. A comparison of T-state and R-state structures of the enzyme explains its cooperative behaviour on ligand binding and the allosteric regulation of its activity. Communication between catalytic sites of the dimer is provided by a change in packing geometry of two helices linking each site with the subunit interface. Activation by AMP or by phosphorylation results in a quaternary conformational change that switches these two helices into the R-state conformation.     

原子核内的夸克分布：Ⅳ EMC效应的复合模型

本文建立了EMC效应的复合模型。计算表明,这一模型能较好地解释整个x_B区的测量数据,特别是与最新实验数据符合很好。     

Structure of the recA protein-ADP complex.

The recA protein catalyses the ATP-driven homologous pairing and strand exchange of DNA molecules. It is an allosteric enzyme: the ATPase activity is DNA-dependent, and ATP-bound recA protein has a high affinity for DNA, whereas the ADP-bound form has a low affinity. In the absence of ATP hydrolysis, recA protein can still promote homologous pairing, apparently through the formation of a triple-stranded intermediate. The exact role of ATP hydrolysis is not clear, but it presumably drives the triplex intermediate towards products. Here we determine the position of bound ADP diffused into the recA crystal. We show that only the phosphates are bound in the same way as in other NTPases containing the G/AXXXXGKT/S motif. We propose that recA protein may change its conformation upon ATP hydrolysis in a manner analogous to one such protein, the p21 protein from the ras oncogene. A model is presented to account for the allosteric stimulation of DNA binding by ATP. The mechanism by which nucleoside triphosphate hydrolysis is coupled to the binding of another ligand in recA protein and p21 may be typical of the large class of NTPases containing this conserved motif.