p53活性四聚体全原子分子动力学分析

p53是一种肿瘤抑制蛋白,对阻碍癌症发展、维持遗传完整性起着至关重要的作用.在细胞核内,4个p53分子通过高度协同的方式、通过DNA结合域与DNA结合,形成稳定的四聚体活性结构,并转录激活或抑制其靶向基因.然而,大多数肿瘤细胞中存在大量p53的突变,其中绝大部分突变发生在p53的DNA结合域,而p53的DNA结合域又是p53形成四聚体活性结构、调控下游靶基因转录的重要区域.本文通过全原子分子动力学模拟,研究了野生型p53四聚体内分子间的相互作用机制.结果表明,位于DNA两侧的对称二聚体是一个稳定的二聚体,在与DNA结合前后都能维持稳定的结构.位于DNA同侧的两个单体依靠两个接触面提供的蛋白-蛋白相互作用和DNA的骨架作用使四聚体活性结构保持稳定,这些相互作用为四聚体的形成机制提供了重要支撑.该工作厘清了p53四聚体在动力学过程中的内部相互作用机制和关键残基,揭示了四聚化过程中各个相互作用界面的关键位点,对于理解p53的抑癌机制、探索有效治癌策略、发展治癌药物具有重要意义.

DNA损伤致p53-Mdm2相互作用的非线性动力学模型(英文)

p53-Mdm2相互作用在DNA损伤的细胞响应方面起着非常重要的作用。最新实验结果表明,在受到各种辐射损伤而引起DNA损伤后,细胞中的p53蛋白浓度在单体细胞和群体细胞情况下,表现为非衰减振荡和衰减振荡两种不同的动力学行为。通过研究p53-Mdm2负反馈回路的非线性动力学,分析了各种(特别是DNA损伤,p53和Mdm2浓度三者之间的)动力学关系,提出了一个能同时描述这两种不同动力学行为的非线性模型。

驱动蛋白力产生机制的研究

驱动蛋白颈链对接过程及其力产生机制的研究,是揭示驱动蛋白结构与功能的关系,认识生物体蛋白质中普遍存在的、高效的能量转化机制和精确的构象变化调控机制的一个基础性课题。本文中,我们对驱动蛋白颈链对接的过程及其力产生机制进行了系统地分析研究。通过分子动力学模拟,得到了处于空态的马达头部的合理结构。在此结构的基础上,通过对颈链对接的启动机制以及具体实现过程、ATP结合引起的马达头部转动到颈链对接过程力传递路径的分析,从动力学上实现了驱动蛋白颈链对接;澄清了颈链对接的启动机制、颈链向马达头部对接的实现机制、驱动蛋白向前行走时的力产生机制、以及驱动蛋白双头力学化学循环调控机制。对文中所讨论的一些关键问题,给出了实验验证的可能方案。本文的研究结果对理解驱动蛋白结构与功能关系、分子马达的力产生机制、做功原理和高效的能量转换机制有重要的参考价值。

Nutlin-3a对p53-MDM2复合物稳定性影响

p53蛋白是一种与细胞周期停滞和细胞凋亡有关的蛋白质.在受到细胞压力或环境扰动后,p53促进下游多个靶基因的转录,介导肿瘤抑制.MDM2是主要的E3泛素连接酶,也是p53的负调控因子.MDM2可促进p53的泛素化和核输出,抑制p53的抑癌活性.因此MDM2对p53的负调控始终是肿瘤治疗中急切需要解决的问题.Nutlin-3a是被证明可以有效抑制p53-MDM2相互作用的小分子抑制剂.本文使用全原子分子动力学模拟,研究Nutlin-3a对p53-MDM2复合物的稳定性的影响.结果表明,通过引起p53和MDM2间Phe19-Gln72的氢键和Glu17-Lys94的盐桥发生的断裂,Nutlin-3a可以削弱p53和MDM2间的相互作用.我们的工作对Nutlin-3a小分子抑制剂的作用机制进行了说明,揭示了抗癌药物Nutlin-3a介导的p53-MDM2复合物亲和力降低的分子机制,并为针对p53蛋白的有效抗癌治疗提供了理论基础.

Oscillatory Activities in Regulatory Biological Networks and Hopf Bifurcation

Exploiting the nonlinear dynamics in the negative feedback loop, we propose a statistical signal-response model to describe the different oscillatory behaviour in a biological network motif. By choosing the delay as a bifurcation parameter, we discuss the existence of Hopf bifurcation and the stability of the periodic solutions of model equations with the centre manifold theorem and the normal form theory. It is shown that a periodic solution is born in a Hopf bifurcation beyond a critical time delay, and thus the bifurcation phenomenon may be important to elucidate the mechanism of oscillatory activities in regulatory biological networks.

便携式智能化相位－幅值综合测试仪

便携式智能相位幅值综合测试仪是一种新型的相位、幅值测量仪表，其性能优异、使用方便、测量准确、一机多用（可测相位、幅值、频率、功率因数），有逐步替代传统仪表的趋势。本文介绍了该综合测试仪的特点、原理、结构、电路以及主程序，并就一些特殊设计和构思作了说明。

Noise transmission and delay-induced stochastic oscillations in biochemical network motifs

With the aid of stochastic delayed-feedback differential equations, we derive an analytic expression for the power spectra of reacting molecules included in a generic biological network motif that is incorporated with a feedback mechanism and time delays in gene regulation. We systematically analyse the effects of time delays, the feedback mechanism, and biological stochasticity on the power spectra. It has been clarified that the time delays together with the feedback mechanism can induce stochastic oscillations at the molecular level and invalidate the noise addition rule for a modular description of the noise propagator. Delay-induced stochastic resonance can be expected, which is related to the stability loss of the reaction systems and Hopf bifurcation occurring for solutions of the corresponding deterministic reaction equations. Through the analysis of the power spectrum, a new approach is proposed to estimate the oscillation period.

Cellular Response to Irradiation

为了探索细胞的发信号系统的非线性的活动，一只 transcriptional 手臂和一只蛋白质相互作用手臂创作了，我们使用一个照耀反应模块学习随机的相互作用的动力学。导出放射的信号和噪音什么时候被合并，被显示出摆动的行为能以一个统一方法被描述。

Stochastic Nature in Cellular Processes

The importance of stochasticity in cellular processes is increasingly recognized in both theoretical andexperimental studies.General features of stochasticity in gene regulation and expression are briefly reviewed in thisarticle,which include the main experimental phenomena,classification,quantization and regulation of noises.Thecorrelation and transmission of noise in cascade networks are analyzed further and the stochastic simulation methodsthat can capture effects of intrinsic and extrinsic noise are described.

Radiation-induced robust oscillation and non-Gaussian fluctuation

There have been many recent studies devoted to the consequences of stochasticity in protein circuitry. Stress conditions, including DNA damage, hypoxia, heat shock, nutrient deprivation, and oncogene activation, can result in the activation and accumulation of p53. Several experimental studies show that oscillations can be induced by DNA damage following nuclear irradiation. To explore the underlying dynamical features and the role of stochasticity, we discuss the oscillatory dynamics in the well-studied regulatory network motif. The fluctuations around the fixed point of a delayed system are Gaussian in the limit of sufficiently weak delayed feedback, and remain Gaussian along a limit cycle when viewed tangential to the trajectory. The experimental results are recapitulated in this study. We illustrate several features of the p53 activities, which are robust when the parameters change. Furthermore, the distribution in protein abundance can be characterized by its non-Gaussian nature.

Initial conformation of kinesin's neck linker

How ATP binding initiates the docking process of kinesin＇s neck linker is a key question in understanding kinesin mechanisms. By exploiting a molecular dynamics method, we investigate the initial conformation of kinesin＇s neck linker in its docking process. We find that, in the initial conformation, the neck linker has interactions with /30 and forms a ＇cover-neck bundle＇ structure with/30. From this initial structure, the formation of extra turns and the docking of the cover- neck bundle structure can be achieved. The motor head provides a forward force on the initial cover-neck bundle structure through ATP-induced rotation. This force, together with the hydrophobic interaction of ILE327 with the hydrophobic pocket on the motor head, drives the formation of the extra turn and initiates the neck linker docking process. Based on these findings, a pathway from ATP binding-induced motor head rotation to neck linker docking is proposed.

High-Spin States in Transuranium Nuclei ^(242,244)Pu

We investigate the structure of yrast bands in the transuranium nuclei ^(242)Pu and ^(244)Pu in the framework of the projected shell model,which is a fully quantum mechanical and microscopic approach.It is found that an appropriate modification of the standard Nilsson spin-orbital parameters in the N =6 proton shell is necessary to correctly describe the high-spin backbending phenomenon in nucleus ^(244)Pu.In order to test whether this modification is correct,the same modified parameters are used to calculate the yrast band of its neighboring isotope ^(242)Pu.It is found that without this modification,a backbending will occur at spin I =20,which is not supported by the experimental data.

Mechanism of Competition between Nutlin3 and p53 for Binding with Mdm2

The tumour suppressor p53 is a transcription factor that regulates multiple biological functions including metabolism, DNA repair, cell cycle arrest, apoptosis and senescence. About half of human cancers show a normal TP53 gene and aberrant overexpression of Mdm2. This fact promotes a promising cancer therapeutic strategy by inhibiting the interactions between p53 and Mdm2. Various inhibitors have been designed to achieve this novel approach for cancer therapy. However, the detailed competition mechanism between these inhibitors and the p53 molecule in their binding process to Mdm2 is still unclear. We investigate this competition mechanism between Nutlin3 and p53 using molecular dynamics simulations. It is found that Nutlin3 binds faster than the p53 molecule to Mdm2 to prevent p53 binding to Mdm2 when Nutlin3 and p53 have equal distance from Mdm2. Nutlin3 can also bind to the p53-Mdm2 complex to disturb and weaken the interactions between p53 and Mdm2. Consequently, p53 cannot bind to Mdm2 and its tumour suppression function is reactivated. These results provide the detailed competition mechanism between Nutlin3 and p53 in their binding to Mdm2. Because the binding site of most other inhibitors to Mdm2 is the same as Nutlin3, therefore this competition mechanism can extend to most inhibitors which target the p53-Mdm2 interaction.

Probing the Dissipation Mechanism in Ternary Reactions of ^197Au＋^197Au by Mean Free Path of Nucleons

the collision of very heavy nuclei ^197Au＋^197Au at 15AMeV has been studied within the improved quantum molecular dynamics model. A class of ternary events satisfying nearly complete balance of mass numbers is selected. The experimental mass distributions for the system ^197Au＋^197Au ternary fission fragments, the heaviest（A1）, the intermediate （A2） and the lightest （A3）, are reproduced well. The mean free path of nucleons in the reaction system is studied and the shorter mean free path is responsible for the ternary fission with three mass comparable fragments, in which the two-body dissipation mechanism plays a dominant role.

Possible Mechanisms of Ternary Fission in the ^197Au＋^197Au System at 15 A MeV

Ternary fission in ^197Au＋^197Au collisions at 15 A MeV is investigated by using the improved quantum molecular dynamical （ImQMD） model. The experimental mass distributions for each of the three fragments are reproduced for the first time without any freely adjusting parameters. The mechanisms of ternary fission in central and semicentral collisions are dynamically studied. In direct prolate ternary fission, two necks are found to be formed almost simultaneously and rupture sequentially in a very short time interval. Direct oblate ternary fission is a very rare fission event, in which three necks are formed and rupture simultaneously, forming three equally sized fragments along space-symmetric directions in the reaction plane. In sequential ternary fission a binary division is followed by another binary fission event after hundreds of fm/c.

核多体系统输运现象的微观理论

首先回顾了描写核多体系统输运现象的一些主要模型和方法,然后介绍了输运现象微观动力学基础研究上一些新的结果,强调了单粒子运动动力学特征在建立集体输运方程和理解超重核合成机制上的重要作用。能量耗散和熵产生的数值计算结果表明,集体运动耗散过程可分为退相干、弛豫和定态等3个阶段,弛豫过程通常表现为非常复杂的反常扩散过程。在这些理论工作的基础上,提出了一种自洽地分离核多体系统集体和单粒子变量的可能途径。

重核三裂变反应过程中的能量耗散

研究了15 Me V/u197Au+197Au体系三裂变反应过程中体系的集体运动动能、核-核相互作用势、集体运动总动能以及核子激发能的演化过程,并讨论了该反应过程的能量耗散问题。通过与两裂变时体系总动能εtot和Θc.m.关联图作对比,初步得出三裂变反应体系的第一次裂变是极端深度非弹性散射过程;进一步分析了三裂变与两裂变反应体系总动能与碰撞参数的关系,发现小碰撞参数下两裂变比三裂变反应耗散的能量多大约150 Me V,大碰撞参数下三裂变比两裂变反应多消耗300 Me V。

DNA损伤致p53-Mdm2相互作用的动力学模型

最新实验结果表明,在受到各种辐射而引起DNA损伤后,在单体细胞和群体细胞情况下,细胞中的p53蛋白浓度表现为非衰减振荡和衰减振荡两种不同的动力学行为.通过研究p53-Mdm2负反馈回路的非线性动力学行为,分析了各种(特别是DNA损伤、p53和Mdm2蛋白浓度三者之间)动力学关系,提出了一个能同时描述这两种不同动力学行为的非线性模型.

中高能重离子弹核碎裂反应研究

通过CR-39核径迹探测器对471 AMeV56Fe和400 AMeV20Ne诱发Al,C和CH2靶反应的弹核碎裂反应截面及出射角度进行了测量,并利用改进的量子分子动力学(ImQMD)模型和描述统计衰变的GEMINI模型对实验结果进行了分析和讨论。实验结果表明,总反应截面与弹核的能量无关,但随着靶核质量的增加而增加。这与其他的实验结果以及Bradt-Peters的半经验理论公式所得结果一致。理论计算和实验测量结果中,分截面出现了明显的奇偶效应。理论计算结果表明,奇偶效应主要产生于受激碎块的衰变过程,其中对效应起着重要作用,而且,主要形成于擦边碰撞的反应中且多来自于同位旋为TZ=0,±0.5的弹核碎块的贡献。产生碎块的同位素分布与弹核的种类有关,与入射能量和靶核的种类没有太大依赖性,其较小的偏转角大部分来自于擦边碰撞产生的较重的类弹碎块的贡献。

Skyrme能量密度泛函在深度垒下熔合反应中的初步应用

基于Skyrme能量密度泛函并对动能密度按扩展的Thomas-Fermi半经典近似展开到四阶项,探索了深度垒下熔合反应的熔合截面急剧下降现象。通过分析熔合反应的入射道势和熔合截面来选择Skyrme参数,进而探索了深度垒下熔合反应与核物质状态方程之间的关系。