Molecular brute-force

Loesch H J and Remscheid A 1990 Brute force in molecular reaction dynamics a novel technique for measuring steric effects J. Chem. Phys. 93 4779-90... 

Molecular dynamics consists of the brute-force solution of Newton s equations of motion. It is necessary to encode in the program the potential energy and force law of interaction between molecules the equations of motion are solved numerically, by finite difference techniques. The system evolution corresponds closely to what happens in real life and allows us to calculate dynamical properties, as well as thennodynamic and structural fiinctions. For a range of molecular models, packaged routines are available, either connnercially or tlirough the academic conmuinity. 

If it is known that a drug must bind to a particular spot on a particular protein or nucleotide, then a drug can be tailor-made to bind at that site. This is often modeled computationally using any of several different techniques. Traditionally, the primary way of determining what compounds would be tested computationally was provided by the researcher s understanding of molecular interactions. A second method is the brute force testing of large numbers of compounds from a database of available structures. 

The molecular dynamics approach has been called a brute-force solution of Newton s equations of motion. [8] One normally starts a simulation using some assumed configuration of the system components, for example, an X-ray... 

Time scales for various motions within biopolymers (upper) and nonbiological polymers (lower). The year scale at the bottom shows estimates of when each such process might be accessible to brute force molecular simulation on supercomputers, assuming that parallel processing capability on supercomputers increases by about a factor of 1,000 every 10 years (i.e., one order of magnitude more than Moore s law) and neglecting new approaches or breakthroughs. Reprinted with permission from H.S. Chan and K. A. Dill. Physics Today, 46, 2, 24, (1993). 

The purpose of this book is to show how the consideration of molecular symmetry can cut short a lot of the work involved in the quantum mechanical treatment of molecules. Of course, all the problems we will be concerned with could be solved by brute force but the use of symmetry is both more expeditious and more elegant. For example, when we come to consider Huckel molecular orbital theory for the trivinylmethyl radical, we will find that if we take account of the molecule s symmetry, we can reduce the problem of solving a 7 x 7 determinantal equation to the much easier one of solving one 3x3 and two 2x2 determinantal equations and this leads to having one cubic and two quadratic equations rather than one seventh-order equation to solve. Symmetry will also allow us immediately to obtain useful qualitative information about the properties of molecules from which their structure can be predicted for example, we will be able to predict the differences in the infra-red and Baman spectra of methane and monodeuteromethane and thereby distinguish between them. 

Clearly, computational resources are not yet to the point that brute force methods will suffice for high-precision calculations. Physical and chemical intuition play an important role in constructing appropriate trial wave functions and, despite the complexity and size of the basis sets used in these calculations, can improve the convergence of the basis significantly. It is important, therefore, to understand the nature of an atomic or molecular system in terms of its physical as well as its more formal mathematical properties. 

The class of problem which we are presenting here can not be done with a reasonable amount of computer time, using brute force techniques. It is necessary, for example, to solve a two-dimensional problem rather than a three dimensional problem. Another example is the problem of molecular diffusion (4,5,6). The usual binary diffusion approximation is inadequate. At the very least total mass is transported in this approximation. The primary difficulty in a general treatment is that of inverting a large (N. x N ) matrix at each time step and for each grid... 

The construction of an MVP-9500 version of the molecular mechanics program which ran faster than the author s PDP-11/40 (FIS) version was an undemanding if tedious process but, as with construction of VPLIB routines, arriving at an efficient rather than brute force coding will take several iterations. 

Two routes have been followed in reaction stereodynamics. One is to orient a molecular reactant in space and see how the reaction cross-section varies with the molecular orientation. This direction has been pioneered in molecular beam experiments using focusing of an electric hexapole field to control the molecular orientation [221-223a]. Numerous studies have applied this technique to electron-transfer reactions of alkaline-earth atoms [223b]. This technique is now complemented by the so-called brute force technique, where polar molecules are oriented in extremely strong electric fields [83]. 

At the other end of the prediction spectrum, is a brute force, ab initio approach one simulates the molecular motions of the polypeptide chain in solution and simply waits for it to spontaneously fold up into its native structure. In effect, one tries to reproduce in the computer the biological folding reaction as it occurs in the cell (or at least the test tube). This very ambitious approach has been carried out for several years by the pioneering Folding Home distributed computing project [13]. It provides not only a structure prediction, but a detailed physical picture of the folding reaction. 

Two difficulties make the "brute force" application of connectivity indices as developed for ordinary molecules [1,2] and reviewed in Section 2.A to polymer chains a hopeless task unless some modifications are made. Firstly, the number of atoms in a typical polymer chain is very large (usually many thousands). Secondly, polymers usually manifest polydispersity in other words, they contain chains of different molecular weights and hence different numbers of atoms. The necessity of taking advantage of the fact that the physical properties of polymers mainly depend on specific short range structural features and interactions, and thus reducing the problem to the calculation of the % values of an appropriate finite molecular system, is clearly seen from the existence of these two major difficulties. 

Combinatorial chemistry has provided the means to synthesize literally billions of molecules, a major step forward in the exploration of molecular space. This random or brute-force approach to the search for new leads has been a major disappointment in its contribution to product pipelines (186) and the sacrifice of quality for quantity (187). However, combinatorial exploration around lead compounds or pharmacophores to generate dedicated libraries, when coupled with high-throughput screening, clearly provides an economical and efficient way to rapidly generate lead compounds (188). 

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