Annual Review of Biophysics and Biomolecular Structure

▪ Abstract Although protein function is thought to depend on flexibility, precisely how the dynamics of the molecule and its environment contribute to catalytic mechanisms is unclear. We review experimental and computational work relating to enzyme dynamics and function, including the role of solvent. The evidence suggests that fast motions on the 100 ps timescale, and any motions coupled to these, are not required for enzyme function. Proteins where the function is electron transfer, proton tunneling, or ligand binding may have different dynamical dependencies from those for enzymes, and enzymes with large turnover numbers may have different dynamical dependencies from those that turn over more slowly. The timescale differences between the fastest anharmonic fluctuations and the barrier-crossing rate point to the need to develop methods to resolve the range of motions present in enzymes on different time- and lengthscales.

R.M. Daniel

R.V. Dunn

J.L. Finney

J.C. Smith

The Role of Dynamics in Enzyme Activity

酶活性中的动力学作用

▪ Abstract Potassium (K + ) channels are tetrameric membrane-spanning proteins that provide a selective pore for the conductance of K + across the cell membranes. These channels are most remarkable in their ability to discriminate K + from Na + by more than a thousandfold and conduct at a throughput rate near diffusion limit. The recent progress in the structural characterization of K + channel provides us with a unique opportunity to understand their function at the atomic level. With their ability to go beyond static structures, molecular dynamics simulations based on atomic models can play an important role in shaping our view of how ion channels carry out their function. The purpose of this review is to summarize the most important findings from experiments and computations and to highlight a number of fundamental mechanistic questions about ion conduction and selectivity that will require further work.

Benoît Roux

Ion Conduction and Selectivity in K<sup>+</sup> Channels

K<sup>+</sup>通道中的离子传导与选择性

The development of single-molecule detection and manipulation has allowed us to monitor the behavior of individual biological molecules and molecular complexes in real time. This approach significantly expands our capability to characterize complex dynamics of biological processes, allowing transient intermediate states and parallel kinetic pathways to be directly observed. Exploring this capability to elucidate complex dynamics, recent single-molecule experiments on RNA folding and catalysis have improved our understanding of the folding energy landscape of RNA and allowed us to better dissect complex RNA catalytic reactions, including translation by the ribosome.

Xiaowei Zhuang

Single-Molecule RNA Science

单分子RNA科学

▪ Abstract Molecular interactions are the language that molecules use to communicate recognition, binding, and regulation, events central to biological control mechanisms. Traditionally, such interactions involve direct, atom-to-atom, noncovalent contacts, or indirect contacts bridged by relatively fixed solvent molecules. Here we discuss a third class of molecular communication that, to date, has received less experimental attention, namely solvent-mediated communication between noncontacting macromolecules. This form of communication can be understood in terms of fundamental, well-established principles (coupled equilibria and linkage thermodynamics) that govern interactions between individual polymers and their solutions. In contrast to simple solutions used in laboratory studies, biological systems contain a multitude of nominally noninteracting biopolymers within the same solution environment. The exquisite control of biological function requires some form of communication between many of these solution components, even in the absence of direct and/or indirect contacts. Such communication must be considered when describing potential mechanisms of biological regulation.

Jens Völker

Kenneth J. Breslauer

Communication Between Noncontacting Macromolecules

非接触大分子间的通信

▪ Abstract Water plays a central role in the structures and properties of biomolecules—proteins, nucleic acids, and membranes—and in their interactions with ligands and drugs. Over the past half century, our understanding of water has been advanced significantly owing to theoretical and computational modeling. However, like the blind men and the elephant, different models describe different aspects of water's behavior. The trend in water modeling has been toward finer-scale properties and increasing structural detail, at increasing computational expense. Recently, our labs and others have moved in the opposite direction, toward simpler physical models, focusing on more global properties—water's thermodynamics, phase diagram, and solvation properties, for example—and toward less computational expense. Simplified models can guide a better understanding of water in ways that complement what we learn from more complex models. One ultimate goal is more tractable models for computer simulations of biomolecules. This review gives a perspective from simple models on how the physical properties of water—as a pure liquid and as a solvent—derive from the geometric and hydrogen bonding properties of water.

Ken A. Dill

Thomas M. Truskett

Vojko Vlachy

Barbara Hribar-Lee

MODELING WATER, THE HYDROPHOBIC EFFECT, AND ION SOLVATION

建模水、疏水效应与离子溶剂化

Accurate methods of computing the affinity of a small molecule with a protein are needed to speed the discovery of new medications and biological probes. This paper reviews physics-based models of binding, beginning with a summary of the changes in potential energy, solvation energy, and configurational entropy that influence affinity, and a theoretical overview to frame the discussion of specific computational approaches. Important advances are reported in modeling protein-ligand energetics, such as the incorporation of electronic polarization and the use of quantum mechanical methods. Recent calculations suggest that changes in configurational entropy strongly oppose binding and must be included if accurate affinities are to be obtained. The linear interaction energy (LIE) and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methods are analyzed, as are free energy pathway methods, which show promise and may be ready for more extensive testing. Ultimately, major improvements in modeling accuracy will likely require advances on multiple fronts, as well as continued validation against experiment.

Michael K. Gilson

Huan-Xiang Zhou

Annu. Rev. Biophys. Biomol. Struct.

Calculation of Protein-Ligand Binding Affinities

蛋白质-配体结合亲和力的计算

Covalent attachment of ubiquitin-like proteins (Ubls) is a predominant mechanism for regulating protein function in eukaryotes. Several structurally related Ubls, such as ubiquitin, SUMO, NEDD8, and ISG15, modify a vast number of proteins, altering their functions in a variety of ways. Ubl modifications can affect the target's half-life, subcellular localization, enzymatic activity, or ability to interact with protein or DNA partners. Generally, these diverse Ubls are covalently attached via their C termini to their targets by parallel, but specific, cascades involving three classes of enzymes known as E1, E2, and E3. Structures are now available for many protein complexes in E1-E2-E3 cascades, revealing a series of modular building blocks and providing mechanistic insights into their functions.

Billy T. Dye

Brenda A. Schulman

Structural Mechanisms Underlying Posttranslational Modification by Ubiquitin-Like Proteins

泛素样蛋白翻译后修饰的结构机制

Many biologically important macromolecules undergo motions that are essential to their function. Biophysical techniques can now resolve the motions of single molecules down to the nanometer scale or even below, providing new insights into the mechanisms that drive molecular movements. This review outlines the principal approaches that have been used for high-resolution measurements of single-molecule motion, including centroid tracking, fluorescence resonance energy transfer, magnetic tweezers, atomic force microscopy, and optical traps. For each technique, the principles of operation are outlined, the capabilities and typical applications are examined, and various practical issues for implementation are considered. Extensions to these methods are also discussed, with an eye toward future application to outstanding biological problems.

William J. Greenleaf

Michael T. Woodside

Steven M. Block

High-Resolution, Single-Molecule Measurements of Biomolecular Motion

高分辨率单分子生物分子运动测量

Recent progress in proteomics suggests that the cell can be conceived as a large network of highly refined, nanomachine-like protein complexes. This working hypothesis calls for new methods capable of analyzing individual protein complexes in living cells and tissues at high speed. Here, we examine whether single-molecule fluorescence (SMF) analysis can satisfy that demand. First, recent technical progress in the visualization, localization, tracking, conformational analysis, and true resolution of individual protein complexes is highlighted. Second, results obtained by the SMF analysis of protein complexes are reviewed, focusing on the nuclear pore complex as an instructive example. We conclude that SMF methods provide powerful, indispensable tools for the structural and functional characterization of protein complexes. However, the transition from in vitro systems to living cells is in the initial stages. We discuss how current limitations in the nanoscopic analysis of living cells and tissues can be overcome to create a new paradigm, nanoscopic biomedicine.

Reiner Peters

Single-Molecule Fluorescence Analysis of Cellular Nanomachinery Components

单分子荧光分析细胞纳米机器组件

Within a population of genetically identical cells there can be significant variation, or noise, in gene expression. Yet even with this inherent variability, cells function reliably. This review focuses on our understanding of noise at the level of both single genes and genetic regulatory networks, emphasizing comparisons between theoretical models and experimental results whenever possible. To highlight the importance of noise, we particularly emphasize examples in which a stochastic description of gene expression leads to a qualitatively different outcome than a deterministic one.

Narendra Maheshri

Erin K. O’Shea

Living with Noisy Genes: How Cells Function Reliably with Inherent Variability in Gene Expression

与嘈杂的基因共存：细胞如何在基因表达的固有变异性中可靠地发挥功能

出版信息	出版商: Annual Reviews Inc.，出版周期: ，期刊类型: book-series，开源期刊: 否
基本数据	创刊年份: 1992，原创研究文献占比: ，自引率:， Gold OA占比:

Annual Review of Biophysics and Biomolecular Structure

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The Role of Dynamics in Enzyme Activity

Ion Conduction and Selectivity in K⁺ Channels

Single-Molecule RNA Science

Communication Between Noncontacting Macromolecules

MODELING WATER, THE HYDROPHOBIC EFFECT, AND ION SOLVATION

Calculation of Protein-Ligand Binding Affinities

Structural Mechanisms Underlying Posttranslational Modification by Ubiquitin-Like Proteins

High-Resolution, Single-Molecule Measurements of Biomolecular Motion

Single-Molecule Fluorescence Analysis of Cellular Nanomachinery Components

Living with Noisy Genes: How Cells Function Reliably with Inherent Variability in Gene Expression

Annual Review of Biophysics and Biomolecular Structure

期刊引文格式

有 1 位以上作者的期刊

有 2 位作者的期刊

有 3 位作者的期刊

有 5 位以上作者的期刊

书籍引用格式

学位论文引用格式

网页引用格式

专利引用格式

手工熬夜修改参考文献？研飞自动匹配期刊，一键轻松成稿，支持 Word/WPS

投稿经验分享

The Role of Dynamics in Enzyme Activity

Ion Conduction and Selectivity in K+ Channels

Single-Molecule RNA Science

Communication Between Noncontacting Macromolecules

MODELING WATER, THE HYDROPHOBIC EFFECT, AND ION SOLVATION

Calculation of Protein-Ligand Binding Affinities

Structural Mechanisms Underlying Posttranslational Modification by Ubiquitin-Like Proteins

High-Resolution, Single-Molecule Measurements of Biomolecular Motion

Single-Molecule Fluorescence Analysis of Cellular Nanomachinery Components

Living with Noisy Genes: How Cells Function Reliably with Inherent Variability in Gene Expression

Ion Conduction and Selectivity in K⁺ Channels