Molecular assemblers: molecular machines performing chemical synthesis

Molecular assemblers were proposed by K. Eric Drexler in 1986, based on the ideas of R. Feynman. In his (quite lurid) book “Engines of Creation: The Coming Era of Nanotechnology” and follow-up publications Drexler proposes molecular machines capable of positioning reactive molecules with atomic precision and to build larger, more sophisticated structures via mechanosynthesis. These imaginative visions started a hot controversy. The debate culminated in a cover story of Chemical & Engineering News in 2003 (ref. 1) with the key question: “Are molecular assemblers – devices capable of positioning atoms and molecules for precisely defined reactions – possible?” with Drexler as the proponent and Nobelist Richard E. Smalley being the opponent. Smalley raised two major objections: the “fat fingers” and the “sticky fingers” problem. To grab and guide each individual atom the assembler must have many nano-fingers. Smalley argued that there is just not enough room in the nanometer-sized reaction region to accommodate all the fingers of all the manipulators necessary to have complete control of the chemistry. The sticky finger issue arises from the problem that …“the atoms of the manipulator hands will adhere to the atom that is being moved. So it will often be impossible to release the building block in precisely the right spot.” Smalley concludes that the fat and the sticky finger problems are fundamental and cannot be avoided. While some of the statements of E. Drexler are bold and probably not very realistic, his ideas are inspiring and might be a good starting point to assess on how far laboratory chemistry has advanced towards real “molecular assemblers” within the last two decades.

Molecular assemblers were proposed by K. Eric Drexler in 1986, based on the ideas of R. Feynman.     

From chemical topology to molecular machines

The chemistry of molecules displaying novel topologies has experienced an explosive development in the course of the last 25 years. The fast growth of this field originates to a large extent from the new templated synthetic methods which allow one to prepare these compounds at a real macroscopic level. Our group, in particular, has proposed a particularly efficient copper(I)-based template synthesis of a large variety of catenanes and rotaxanes at an early stage, participating in the revival of molecular topology. One of the highlights of the field has been the synthesis of the trefoil knot, a particularly challenging target. This object is not only an aesthetically attractive molecule but it also displays interesting properties in relation to coordination chemistry and chirality. A highly promising extension of molecular topology is that of molecular machines. By combining the specific properties of catenanes and rotaxanes, i.e., marked flexibility and propensity to undergo large amplitude motions, and coordination chemistry, it has been possible to elaborate and study a large variety of molecular machines. A recent example is that of an adjustable receptor, based on a [3]rotaxane attached to two mobile porphyrinic plates. This compound and related molecules will lead to “molecular presses” and, eventually, to molecular machines usable in solution to catalyse reactions or change the conformation of given substrates.     

Molecular machines operated by light

The bottom-up construction and operation of machines and motors of molecular size is a topic of great interest in nanoscience, and a fascinating challenge of nanotechnology. Researchers in this field are stimulated and inspired by the outstanding progress of molecular biology that has begun to reveal the secrets of the natural nanomachines which constitute the material base of life. Like their macroscopic counterparts, nanoscale machines need energy to operate. Most molecular motors of the biological world are fueled by chemical reactions, but research in the last fifteen years has demonstrated that light energy can be used to power nanomachines by exploiting photochemical processes in appropriately designed artificial systems. As a matter of fact, light excitation exhibits several advantages with regard to the operation of the machine, and can also be used to monitor its state through spectroscopic methods. In this review we will illustrate the design principles at the basis of photochemically driven molecular machines, and we will describe a few examples based on rotaxane-type structures investigated in our laboratories.      

The geometric minimum action method for computing minimum energy paths

An algorithm is proposed to calculate the minimum energy path (MEP). The algorithm is based on a variational formulation in which the MEP is characterized as the curve minimizing a certain functional. The algorithm performs this minimization using a preconditioned steepest-descent scheme with a reparametrization step to enforce a constraint on the curve parametrization.     

Coordinate reduction for exploring chemical reaction paths

The potential energy surface for the reaction of a typical molecular system composed of N atoms is defined uniquely by 3N-6 coordinates. These coordinates can be defined by the Cartesian coordinates of the atomic centers (minus overall translation and rotation), or a set of internally defined coordinates such as bond stretches, angle bends, and torsions. By applying principal component analysis to the geometries along a reaction path, a reduced set of coordinates, d ≪ 3N-6, can be obtained. This reduced set of coordinates can reproduce the changes in geometry along the reaction path with chemical accuracy and may help improve the efficiency of reaction path optimization algorithms.     

The application of symbolic computing to chemical kinetic reaction schemes

Given a reaction mechanism we show how a symbolic computation approach can be used to develop the kinetic equations by identifying the reaction scheme with an equivalent matrix. Our method is also applicable in cases where the stoichiometric matrix approach fails. The specific algorithm that is written applies to schemes where individual reactions are at most ternary, but the way to generalize the procedure is also discussed. By using symbolic computing it is possible to determine general properties of the system. We demonstrate this by showing how to use the matrix to determine the system's conservation laws, which in turn can be used to reduce the number of equations in the system. As another application it is shown how to determine some of the species which have a zero equilibrium state. To illustrate the procedure, example reaction schemes are investigated.     

Molecular chaperones--cellular machines for protein folding

Proteins are linear polymers synthesized by ribosomes from activated amino acids. The product of this biosynthetic process is a polypeptide chain, which has to adopt the unique three-dimensional structure required for its function in the cell. In 1972, Christian Anfinsen was awarded the Nobel Prize for Chemistry for showing that this folding process is autonomous in that it does not require any additional factors or input of energy. Based on in vitro experiments with purified proteins, it was suggested that the correct three-dimensional structure can form spontaneously in vivo once the newly synthesized protein leaves the ribosome. Furthermore, proteins were assumed to maintain their native conformation until they were degraded by specific enzymes. In the last decade this view of cellular protein folding has changed considerably. It has become clear that a complicated and sophisticated machinery of proteins exists which assists protein folding and allows the functional state of proteins to be maintained under conditions in which they would normally unfold and aggregate. These proteins are collectively called molecular chaperones, because, like their human counterparts, they prevent unwanted interactions between their immature clients. In this review, we discuss the principal features of this peculiar class of proteins, their structure-function relationships, and the underlying molecular mechanisms.     

Strategies for computing chemical reactivity indices

 Two recent articles [(2000) J Am Chem Soc 122: 2010, (2001) J Am Chem Soc 123: 2007] have explored electron-density-based and external-potential-based chemical reactivity indices. In this article, methods are presented for computing these indices from the output of a Kohn–Sham density functional theory calculation. Received: 18 October 2000 / Accepted: 4 April 2001 / Published online: 9 August 2001     

Optimal transition paths of stochastic chemical kinetic systems

We present a new framework for finding the optimal transition paths of metastable stochastic chemical kinetic systems with large system sizes. The optimal transition paths are identified, in terms of reaction advancement coordinates, to be the most probable paths according to large deviation theory for the limiting dynamics governed by stochastic differential equations. Dynamical equations for the optimal transition paths are obtained using the variational principle. A multiscale minimum action method is proposed as a numerical scheme to solve the optimal transition paths. Applications to the toggle switch model are presented.     

化学反应处理的计算模型

介绍了一种将同类反应上升为合成反应知识和在计算机上实现反合成分析的方法,反合成分析是合成设计中最关键的一步,在本工作中采用了基于谋略键寻找的合成设计方法。它有逻辑宜于在计算机上实现的优点。为了实现这个方法,我们首次提出了一种能中肯地描述合成反应的计算模型—反应知识的分类模型。这一模型由三条规则定义：规则A-反应类型;规则B-发生反应的外部条件;规则C-不适宜采用这个反应的情况;这种计算模型能够将海量反应数据中最重要最基本的信息提炼出来,转换成计算机能处理的知识。它也包含有反应适用范围的信息,从而提高了析分过程的外推能力。     

Molecular reactors and machines: applications, potential, and limitations

Molecular reactors are miniature vessels for the assembly of reactants at the molecular level, in order to change the nature of chemical transformations. It seems probable that those that will find most immediate applications are those that change product ratios or give products which would not readily form in the absence of the reactors, and thereby afford easy access to materials that are otherwise difficult to obtain. Molecular machines consist of interrelated parts with separate functions and perform some kind of work, at the molecular level. Practical examples are likely to be relatively uncomplicated and not based on individual functions of single-molecule devices. Instead they will probably rely on extensive redundancy of the molecular components and their interactions and reactions, as well as of the machines themselves.     

Molecular tensile machines: intrinsic acceleration of disulfide reduction by dithiothreitol

Significant tension on the order of 1 nN is self-generated along the backbone of bottlebrush macromolecules due to steric repulsion between densely grafted side chains. The intrinsic tension is amplified upon adsorption of bottlebrush molecules onto a substrate and increases with grafting density, side chain length, and strength of adhesion to the substrate. These molecules were employed as miniature tensile machines to study the effect of mechanical force on the kinetics of disulfide reduction by dithiothreitol (DTT). For this purpose, bottlebrush macromolecules containing a disulfide linker in the middle of the backbone were synthesized by atom transfer radical polymerization (ATRP). The scission reaction was monitored through molecular imaging by atomic force microscopy (AFM). The scission rate constant increases linearly with the concentration of DTT and exponentially with mechanical tension along the disulfide bond. Moreover, the rate constant at zero force is found to be significantly lower than the reduction rate constant in bulk solution, which suggests an acidic composition of the water surface with pH = 3.7. This work demonstrates the ability of branched macromolecules to accelerate chemical reactions at specific covalent bonds without applying an external force.     

Chemical oscillations and Turing patterns in a generalized two-variable model of chemical self-replication

Chemical self-replication of oligonucleotides and helical peptides show the so-called square root rate law. Based on this rate we extend our previous work on ideal replicators to include the square root rate and other possible nonlinearities, which we couple with an enzimatic sink. Although the nonlinearity is necessary for complex dynamics, the nature of the sink is the essential feature in the mechanism that allows temporal and spatial patterns. We obtain exact general relations for the Poincare-Adronov-Hopf and Turing bifurcations, and our generalized results include the Higgins, autocatalator, and templator models as specific cases.     

Molecular machines: synthesis and characterization of two prototypes of molecular wheelbarrows

Technomimetic molecules are molecules designed to imitate macroscopic objects at the molecular level, also transposing the motions that these objects are able to undergo. This article focuses on the synthesis of two polyaromatic hydrocarbons designed by analogy with macroscopic wheelbarrows. The molecular wheelbarrows are synthesized following a modular strategy based on sequential double Knoevenagel and Diels-Alder reactions. Our strategy allowed to easily vary the chemical nature of the handles, which is crucial for subsequent manipulation with an STM tip.     

Molecular conductance: chemical trends of anchoring groups

Combining density functional theory calculations for molecular electronic structure with a Green function method for electron transport, we calculate from first principles the molecular conductance of benzene connected to two Au leads through different anchoring atoms-S, Se, and Te. The relaxed atomic structure of the contact, different lead orientations, and different adsorption sites are fully considered. We find that the molecule-lead coupling, electron transfer, and conductance all depend strongly on the adsorption site, lead orientation, and local contact atomic configuration. For flat contacts the conductance decreases as the atomic number of the anchoring atom increases, regardless of the adsorption site, lead orientation, or bias. For small bias this chemical trend is, however, dependent on the contact atomic configuration: an additional Au atom at the contact with the (111) lead changes the best anchoring atom from S to Se, although for large bias the original chemical trend is recovered.     

Bifurcation diagrams and Turing patterns in a chemical self-replicating reaction-diffusion system with cross diffusion

Chemical self-replication of oligonucleotides and helical peptides exhibits the so-called square root rate law. Based on this rate we extend our previous work on ideal replicators to include the square root rate and other possible nonlinearities, which we couple with an enzymatic sink. For this generalized model, we consider the role of cross diffusion in pattern formation, and we obtain exact general relations for the Poincare-Adronov-Hopf and Turing bifurcations, and our generalized results include the Higgins, Autocatalator, and Templator models as specific cases.     

Simplified and improved string method for computing the minimum energy paths in barrier-crossing events

We present a simplified and improved version of the string method, originally proposed by E et al. [Phys. Rev. B 66, 052301 (2002)] for identifying the minimum energy paths in barrier-crossing events. In this new version, the step of projecting the potential force to the direction normal to the string is eliminated and the full potential force is used in the evolution of the string. This not only simplifies the numerical procedure, but also makes the method more stable and accurate. We discuss the algorithmic details of the improved string method, analyze its stability, accuracy and efficiency, and illustrate it via numerical examples. We also show how the string method can be combined with the climbing image technique for the accurate calculation of saddle points and we present another algorithm for the accurate calculation of the unstable directions at the saddle points.     

Validated computing approach for high-pressure chemical and multiphase equilibrium

For the computation of chemical and phase equilibrium at constant temperature and pressure, there have been proposed a wide variety of problem formulations and numerical solution procedures, involving both direct minimization of the Gibbs energy and the solution of equivalent nonlinear equation systems. Still, with very few exceptions, these methodologies may fail to solve the chemical and phase equilibrium problem correctly. Nevertheless, there are many existing solution methods that are extremely reliable in general and fail only occasionally. To take good advantage of this wealth of available techniques, we demonstrate here an approach in which such techniques can be combined with procedures that have the power to validate results that are correct, and to identify results that are incorrect. Furthermore, in the latter case, corrective feedback can be provided until a result that can be validated as correct is found. The validation procedure is deterministic, and provides a mathematical and computational guarantee that the global minimum in the Gibbs energy has been found. To demonstrate this validated computing approach to the chemical and phase equilibrium problem, we present several examples involving reactive and nonreactive components at high pressure, using cubic equation-of-state models.