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首页> 外文学位 >Unraveling the complexity of biological processes from protein native dynamics to cell motility in molecular simulations.
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Unraveling the complexity of biological processes from protein native dynamics to cell motility in molecular simulations.

机译：在分子模拟中揭示从蛋白质天然动力学到细胞运动的生物过程的复杂性。

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摘要

This dissertation consists of two major parts. Both are dedicated to studying biological molecular processes with computer simulations, but differ in the scale of the studied processes. In one project we investigated the dynamics of cellular organelles involved in cell motility -- the filopodia. The other project is zooming in to the scale of single molecule, elucidating the organization of protein molecule native state.;Some motile cells use special fingerlike probes of their environment for guiding their motion called filopodia. They are bundles of parallel actin filaments protruding from the cell body and enveloped by cell's membrane. They are highly dynamic, constantly growing an retracting, randomly, or in response to the change in the environment. These dynamics are governed by the cell's regulatory proteins and by external chemical cues or mechanical obstacles. The previous models predicted that a filopodium grows to a stationary length of about 1 mum with miniscule fluctuations around. (i) We found that capping proteins (they attach to the barbed ends of actin filaments and stop polymerization) can induce macroscopic oscillation of filopodial length -- the growth-retraction cycles. The retraction can be complete. This is the first model that predicts finite lifetimes for filopodia. The lifetimes are consistent with experimental observations. (ii) In the model, however, the maximal filopodial lengths of several microns are still limited by the diffusional transport of actin monomers to the filopodial tip and are far below experimentally observed lengths of up to 100 mum. Assuming the obvious solution for the problem of slow transport in cell, the molecular motors, that are known to be present inside filopodia, we found that a naive addition of motors does not increase the lengths much. In order to have an efficient active transport, two rules must be observed: the motors should not sequester the cargo and the rails for motors should be kept from being clogged by motors. Protein Ena/VASP that is known to be actively transported to the filopodial tip by molecular motors may be a way to fight sequestration.;On the scale of a single macromolecule we studied the organization of protein native state. It is not a single structure, but an ensemble of constantly interconverting conformations. It is essential for a deep insight into protein functioning to know thermodynamics of these substates and dynamical regime of their exploration. (i) In all-atom MD simulations we constructed a 2D free energy surface for a protein Trp-cage and using the FES for Brownian dynamics investigated the nature of dynamical behavior of Trp-cage in its native state. We found that the dynamical regime is borderline between liquid and supercooled liquid. (ii) We developed a general technique for calculating free energy difference between two polymer conformations in explicit solvent simulations and used the Trp-cage 2D FES for testing of this technique, revealing remarkable accuracy and computation efficiency.
机译：本文主要分为两个部分。两者都致力于通过计算机模拟研究生物分子过程，但是所研究过程的规模不同。在一个项目中，我们研究了参与细胞运动的细胞器-丝足运动的动力学。另一个项目是放大单分子的规模，阐明蛋白质分子天然状态的组织。一些运动细胞使用其周围环境的特殊指状探针来引导其运动，称为丝状伪足。它们是从细胞体伸出并被细胞膜包裹的平行肌动蛋白丝束。它们具有很高的动态性，会随环境的变化而不断增加，收缩，随机地增长。这些动态是由细胞的调节蛋白和外部化学提示或机械障碍控制的。先前的模型预测，假单胞菌会生长到大约1毫米的固定长度，周围的波动很小。 （i）我们发现加帽蛋白（它们附着在肌动蛋白丝的带刺末端并停止聚合）可以诱导丝虫长度的宏观振荡-生长-收缩周期。收回可以完成。这是第一个预测丝状伪足寿命有限的模型。寿命与实验观察结果一致。 （ii）然而，在该模型中，数微米的最大伞尾长度仍然受到肌动蛋白单体向伞尾尖扩散扩散的限制，并且远低于实验观察到的最长100毫米的长度。假定存在于丝状伪足中的分子马达是细胞中慢速运输问题的明显解决方案，我们发现单纯添加马达不会显着增加细胞长度。为了有效地进行主动运输，必须遵守两个规则：电动机不应隔离货物，并且应防止电动机的导轨被电动机阻塞。已知通过分子马达将Ena / VASP蛋白质主动转运到丝虫的尖端可能是对抗螯合的一种方法。在单个大分子的尺度上，我们研究了蛋白质天然状态的组织。它不是单个结构，而是不断相互转换构象的集合。深入了解蛋白质功能对于了解这些亚状态的热力学及其探索的动力学机制至关重要。 （i）在全原子MD模拟中，我们为蛋白Trp-笼构建了二维自由能表面，并使用FES进行了布朗动力学研究，研究了Trp-笼在其原始状态下的动力学行为。我们发现动力学机制是液体和过冷液体之间的边界。 （ii）我们开发了一种用于在显式溶剂模拟中计算两种聚合物构象之间的自由能差的通用技术，并使用Trp-cage二维FES对该技术进行了测试，从而显示出显着的准确性和计算效率。

著录项

  • 作者

    Zhuravlev, Pavel I.;

  • 作者单位

    The University of North Carolina at Chapel Hill.;

  • 授予单位 The University of North Carolina at Chapel Hill.;
  • 学科 Chemistry Physical.;Biophysics General.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 133 p.
  • 总页数 133
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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