Co-operativity in biological machines

McClare has recently discussed the properties of machines which operate too fast for there to be appreciable thermalization between components. We argue that co-operative behaviour is likely in those machines and that if there is co-operativity, the machine cannot be treated as the superposition of a large number of “molecular energy machines”. This point may be relevant to models of muscle contraction.     

Structural and organisational conditions for being a machine

Although the analogy between macroscopic machines and biological molecular devices plays an important role in the conceptual framework of both neo-mechanistic accounts and nanotechnology, it has recently been claimed that certain complex molecular devices (consisting of biological or synthetic macromolecular aggregates) cannot be considered machines since they are subject to physicochemical forces that are different from those of macroscopic machines. However, the structural and physicochemical conditions that allow both macroscopic machines and microscopic devices to work and perform new functions, through a combination of elemental functional parts, have not yet been examined. In order to fill this void, this paper has a threefold aim: first, to clarify the structural and organisational conditions of macroscopic machines and microscopic devices; second, to determine whether the machine-like analogy fits nanoscale devices; and third, to assess whether the machine-like analogy is appropriate for describing the behaviour of some biological macromolecules. Finally, the paper gives an account of ‘machine’ which, while acknowledging the physicochemical and organisational differences between man-made machines and biological microscopic devices, nevertheless identifies a common conceptual core that allows us to consider the latter ‘machines’.     

Biophysics; fifty years after Schrödinger

E. Schrödinger described his mechanistic view on life in his book “What is Life?” published in 1944. H. Yukawa stated that life is like a building of bricks. Is life understandable in this manner?In 1950–1960 the generation of structure and function in living cells was shown to be analyzable, step by step, within the theoretical framework of physics. In the 1970's the concept of a molecular machine or unit machine in living cells was clearly presented and the effort to experimentally define unit machines was promoted. Recently, new techniques to directly observe their behaviors have been developed. The machines are not always rigid. In sliding machines, the influx-efflux coupling has been found to be loose. For loose coupling, intramachine flexibility seems to be useful.Living cells can be regarded as an organized system composed of many unit machines, some of which exhibit deterministic behaviors while others exhibit probabilistic behaviors. The cells do not always show a definite response to a given input. We need new statistical mechanics for the study of unit machines and their systems which have complex spatial and temporal structures. They may have a mechanism beyond a simple building of bricks.     

Theory of molecular machines. I. Channel capacity of molecular machines

Like macroscopic machines, molecular-sized machines are limited by their material components, their design, and their use of power. One of these limits is the maximum number of states that a machine can choose from. The logarithm to the base 2 of the number of states is defined to be the number of bits of information that the machine could "gain" during its operation. The maximum possible information gain is a function of the energy that a molecular machine dissipates into the surrounding medium (Py), the thermal noise energy which disturbs the machine (Ny) and the number of independently moving parts involved in the operation (dspace): Cy = dspace log2 [( Py + Ny)/Ny] bits per operation. This "machine capacity" is closely related to Shannon's channel capacity for communications systems. An important theorem that Shannon proved for communication channels also applies to molecular machines. With regard to molecular machines, the theorem states that if the amount of information which a machine gains is less than or equal to Cy, then the error rate (frequency of failure) can be made arbitrarily small by using a sufficiently complex coding of the molecular machine's operation. Thus, the capacity of a molecular machine is sharply limited by the dissipation and the thermal noise, but the machine failure rate can be reduced to whatever low level may be required for the organism to survive.     

ATP-dependent proteases of bacteria: recognition logic and operating principles

ATP-powered AAA+ proteases degrade specific proteins in intracellular environments occupied by thousands of different proteins. These proteases operate as powerful molecular machines that unfold stable native proteins before degradation. Understanding how these enzymes choose the "right" protein substrates at the "right" time is key to understanding their biological function. Recently, proteomic approaches have identified numerous substrates for some bacterial enzymes and the sequence motifs responsible for recognition. Advances have also been made in elucidating the mechanism and impact of adaptor proteins in regulating substrate choice. Finally, recent biochemical dissection of the ATPase cycle and its coupling to protein unfolding has revealed fundamental operating principles of this important, ubiquitous family of molecular machines.     

A comprehensive comparison of random forests and support vector machines for microarray-based cancer classification

Background  

Cancer diagnosis and clinical outcome prediction are among the most important emerging applications of gene expression microarray technology with several molecular signatures on their way toward clinical deployment. Use of the most accurate classification algorithms available for microarray gene expression data is a critical ingredient in order to develop the best possible molecular signatures for patient care. As suggested by a large body of literature to date, support vector machines can be considered "best of class" algorithms for classification of such data. Recent work, however, suggests that random forest classifiers may outperform support vector machines in this domain.     

Mobile DNA elements: controlling transposition with ATP-dependent molecular switches

Nucleotide-binding proteins are often used as molecular switches to control the assembly or activity of macromolecular machines. Recent work has revealed that such molecular switches also regulate the spread of some mobile DNA elements. Bacteriophage Mu and the bacterial transposon Tn7 each use an ATP-dependent molecular switch to select a new site for insertion and to coordinate the assembly of the transposition machinery at that site. Strong parallels between these ATP-dependent transposition proteins and other well-characterized molecular switches, such as Ras and EF-Tu, have emerged.     

The future is hybrid

On the occasion of the 50th anniversary of the Journal of Structural Biology, we review some of the major advances that have taken place in molecular and cellular structural biology over this timeframe and consider some current trends, as well as promising new directions. While the primary experimental techniques of X-ray diffraction, electron microscopy and NMR spectroscopy continue to improve and other powerful new techniques have come on-line, it appears that the most comprehensive analyses of large, dynamic, macromolecular machines will rely on integrated combinations of different methodologies, viz. "hybrid approaches". The same prospect applies to the challenge of integrating observations of isolated macromolecules with data pertaining to their distributions and interaction networks in living cells. Looking ahead, computation in its diverse aspects may be expected to assume an increasingly important role in structural biology, as the prediction of molecular structures, the computation of dynamic properties, and quantitative time-resolved models of intracellular molecular populations (structural systems biology) move towards functional maturity.     

体外多酶分子机器的现状和最新进展

体外多酶分子机器遵循所设计的多酶催化路径,将若干种纯化或部分纯化的酶元件进行合理的优化与适配,高效地在体外将特定的底物转化为目标化合物。体外多酶分子机器反应系统呈现元件化和模块化的特点,在设计、组装和调控方面具有较高的自由度。近年来,体外多酶分子机器在实现反应过程的精准调控和提高产品得率方面的优势逐渐体现,展示了其在生物制造领域重要的应用潜力。对体外多酶分子机器的相关研究已成为合成生物学的一个重要分支领域,日益受到广泛的关注。文中系统地综述了基于酶元件/模块的体外多酶分子机器的构建策略,以及改善该分子机器中酶元件/模块之间适配性的研究进展,并分析了该生物制造平台的发展前景与挑战。     

Electron cryomicroscopy of biological machines at subnanometer resolution

Advances in electron cryomicroscopy (cryo-EM) have made possible the structural determination of large biological machines in the resolution range of 6-9 angstroms. Rice dwarf virus and the acrosomal bundle represent two distinct types of machines amenable to cryo-EM investigations at subnanometer resolutions. However, calculating the density map is only the first step, and much analysis remains to extract structural insights and the mechanism of action in these machines. This paper will review the computational and visualization methodologies necessary for analysis (structure mining) of the computed cryo-EM maps of these machines. These steps include component segmentation, averaging based on local symmetry among components, density connectivity trace, incorporation of bioinformatics analysis, and fitting of high-resolution component data, if available. The consequences of these analyses can not only identify accurately some of the secondary structure elements of the molecular components in machines but also suggest structural mechanisms related to their biological functions.     

Fluctuation as a tool of biological molecular machines

The mechanism for biological molecular machines is different from that of man-made ones. Recently single molecule measurements and other experiments have revealed unique operations where biological molecular machines exploit thermal fluctuation in response to small inputs of energy or signals to achieve their function. Understanding and applying this mechanism to engineering offers new artificial machine designs.     

Small heat shock proteins, protein degradation and protein aggregation diseases

Small heat shock proteins have been characterized in vitro as ATP-independent molecular chaperones that can prevent aggregation of un- or mis-folded proteins and assist in their refolding with the help of ATP-dependent chaperone machines (e.g., the Hsp70 proteins). Comparison of the functionality of the 10 human members of the small HSPB family in cell models now reveals that some members function entirely differently and independently from Hsp70 machines. One member, HSPB7, has strong activities to prevent toxicity of polyglutamine-containing proteins in cells and Drosophila, and seems to act by assisting the loading of misfolded proteins or small protein aggregates into autophagosomes.     

Self-organization versus watchmaker: molecular motors and protein translocation

Generation of directional movement at the molecular scale is a phenomenon crucial for biological organization and dynamics. It is traditionally described in mechanistic terms, in consistency with the conventional machine-like image of the cell. The designated and highly specialized protein machines and molecular motors are presumed to bring about most of cellular motion. A review of experimental data suggests, however, that uncritical adherence to mechanistic interpretations may limit the ability of researchers to comprehend and model biology. Specifically, this article illustrates that the interpretation of molecular motors and protein translocation in terms of stochasticity and self-organization appears to provide a more adequate and fruitful conceptual framework for understanding of biological organization at the molecular scale.     

Visions for novel biophysical elucidations of extracellular matrix networks

The extracellular matrix consists of multifunctional molecules, which are composed of a large numbers of different domains. Clearly these domains and even the entire molecules do not function independently as isolated species, but interact with each other in large networks. In many cases specific regions of the networks may be considered as molecular machines in which the different molecules are arranged in highly defined spatial structures and act in a dynamic, concerted fashion. At present most structural information is limited to single molecules, and dynamics have been measured mainly for pairs of interacting partners in solution. Work needs to be extended to large integrated systems and the functions of molecular machines need to be explored. Electron tomography, fluorescence resonance energy transfer, and other biophysical techniques are very promising.     

Primitive Molecular Machine Scenario for the Origin of the Three Base Codon Composition

We set up a scenario for the operation of primordial synthesis machines operating in outer space quasi one dimensional channels, where polymers interact with fixed particles. The scheme allows for polymerization, translocation and translation. We will show that under very general conditions the particle/polymer interaction potential has spatial regularities with an average distance of three between neighboring minima. We present a model that exhibits how primitive molecular machines may convert the structural properties of the potential into locomotion regularities. On average, polymer movement takes place by shifts with long time intervals every three displacements. We argue that this feature is generic and lies at the origin of the three base codon composition.     

Continuous recycling: a mechanism for modulatory signal transduction

Modulatory signal transduction commonly requires efficient "on demand" assembly of specific multicomponent cellular machines that convert signals to cellular actions. This article suggests that for these signaling machines to detect and respond to fluctuations in signal strength, they must be continuously disassembled in an energy-dependent process that probably involves molecular chaperones.     

Linking structural change with functional regulation-insights from mass spectrometry

A wide range of biophysical approaches has been applied to structural biology, all with the same overall goal-to understand the molecular machines that allow cells to function. While knowledge of the identity and composition of component protein subunits is an important foundation for understanding these macromolecular complexes it has become increasingly clear that knowledge of the exact composition alone is insufficient for understanding dynamic interactions and regulatory mechanisms. In this review we focus on recent developments of mass spectrometry (MS) that allow us to unravel the functional 'secrets' of non-covalent molecular machines.