Molecular studies future directions

How modeling has been useful in the crystal structure analysis of polysaccharides—and how it could lead to a better understanding of other condensed j)hase states—can be illustrated with structural worK done on cellulose. It is one of the world s most important and widely used raw materials whose structure, properties, derivatives, and transformations remain under continuous study. Some of the results, problems, and indications of future directions resulting from the study of its crystalline structure—and the attendant roles for molecular modeling—are briefly described in the following. 

Two types of information are obtained from any molecular mechanics study, the minimum value of the strain energy and the structure associated with that minimum. Agreement between the energy-minimized and experimental (crystallographic) structures has often been used as the primary check on the validity of the force field and to refine the force field further, but often little predictive use has been made of the structures obtained. As force fields become more reliable, the potential value of structure predictions increases. More importantly, when no unequivocal determination of a structure is available by experimental methods then structure prediction may be the only means of obtaining a three-dimensional model of the molecule. This is often the case, for instance, in metal-macromolecule adducts, and structures obtained by molecular mechanics can be a genuine aid in the visualization of these interactions. In this chapter we consider the ways in which structure prediction by molecular mechanics calcluations has been used, and point to future directions. 

In each section on the different ion channels, some unresolved issues and future directions will be addressed. In general, little is known about the precise molecular structures of the ion channels (e.g., K+ channels) in smooth muscle and our knowledge of endogenous agents as well as key signal transduction pathways that may modulate smooth muscle ion channels is far from complete. Further, as indicated previously, the modulation and expression of ion channels vary with the type of, and even within (e.g., large versus small arteries), smooth muscle. Studies on K+ channels in nonvascular types of smooth muscle will be discussed if similar material from arterial smooth muscle is limited. 

However, it is still unclear how the efficiencies and resolutions of MIP monoliths compare to other methods of capillary fabrication using molecularly imprinted polymers. Future studies that directly compare the chromatographic results obtained using the same imprinting system under different preparation techniques (i.e., packed columns, coated thin films, immobilized particles, and monoliths) have... 

Synthetic methods have been developed to prepare twisted polyarenes with diverse structural features. A large number of X-ray structures have been reported, allowing direct measurements of the extent of distortion from planarity. However, the use of these twisted compounds for synthetic applications remains underdeveloped. While limited success has been achieved in using optically active twisted polyarenes as catalysts for asymmetric induction, a systematic study of this potentially fruitful area has not been undertaken. Molecular recognition is another area that is still in its infancy. Optical and electronic properties have not been exploited. However, there is no reason to believe that the chemistry of twisted polyarenes will not be as fruitful in the future as has been observed over the past 70 years. Because the future direction of the development of this fascinating class of compounds can barely be imagined, success can come from a wide variety of areas. 

In 1985, Car and Parrinello published a seminal article on an Unified approach for molecular dynamics and density functional theory Phys. Rev. Lett. 5S (1985) 2471). This paper established a basis for parameter-firee molecular dynamics simulations in which all the interactions are calculated on the fly via a first-principles quantum mechanical method. In the 15 years of its existence, the Car-Parrinello method has found widespread applications that expanded rapidly from physics to chemistry and, most recently, even into biology. In this article, the foundations of the method in its most common implementation, the one based on density functional theory, plane wave basis sets and pseudopotentials are described and extensions to the original scheme are outlined. The current power of Car-Parrinello simulations is illustrated by presenting selected case studies and possible future directions are sketched in the final outlook. 

Although essentially all studies to date using PRISM and the molecular closures have involved macromolecules, it is conceivable such closures may be of value even for small or intermediate-sized flexible and/or rigid molecules. A careful documentation of the accuracy of the new molecular closures as a broad function of thermodynamic state and molecular fluid type remains an important future direction. In addition, recent interesting alternative approaches to liquid theory for polymer mixtures with attractions have been developed within the general PRISM framework by Melenkevitz and Curro based on the optimized RPA(ORPA) approach, and Donley et. ah " based on density functional theory and also from a field-theoretic perspective by Chandler. Application of these approaches to treat the effect of attractive interactions on fluid structure and phase transitions remains to be worked out. 

At the same time we have illustrated with examples of clusters that the theoretical approaches involving the coupling between electronic structure and motion of nuclei are useful tools removing the border between quantum chemistry and molecular dynamics. The development of new methods allowing the study of time-dependent phenomena involving electronic excitation and motion of nuclei might become an attractive future direction of computational chemistry. 

Clusters are intennediates bridging the properties of the atoms and the bulk. They can be viewed as novel molecules, but different from ordinary molecules, in that they can have various compositions and multiple shapes. Bare clusters are usually quite reactive and unstable against aggregation and have to be studied in vacuum or inert matrices. Interest in clusters comes from a wide range of fields. Clusters are used as models to investigate surface and bulk properties [2]. Since most catalysts are dispersed metal particles [3], isolated clusters provide ideal systems to understand catalytic mechanisms. The versatility of their shapes and compositions make clusters novel molecular systems to extend our concept of chemical bonding, stmcture and dynamics. Stable clusters or passivated clusters can be used as building blocks for new materials or new electronic devices [4] and this aspect has now led to a whole new direction of research into nanoparticles and quantum dots (see chapter C2.17). As the size of electronic devices approaches ever smaller dimensions [5], the new chemical and physical properties of clusters will be relevant to the future of the electronics industry. 

Detailed reaction dynamics not only require that reagents be simple but also that these remain isolated from random external perturbations. Theory can accommodate that condition easily. Experiments have used one of three strategies. (/) Molecules ia a gas at low pressure can be taken to be isolated for the short time between coUisions. Unimolecular reactions such as photodissociation or isomerization iaduced by photon absorption can sometimes be studied between coUisions. (2) Molecular beams can be produced so that motion is not random. Molecules have a nonzero velocity ia one direction and almost zero velocity ia perpendicular directions. Not only does this reduce coUisions, it also aUows bimolecular iateractions to be studied ia intersecting beams and iacreases the detail with which unimolecular processes that can be studied, because beams facUitate dozens of refined measurement techniques. (J) Means have been found to trap molecules, isolate them, and keep them motionless at a predetermined position ia space (11). Thus far, effort has been directed toward just manipulating the molecules, but the future is bright for exploiting the isolated molecules for kinetic and dynamic studies. 

To extract the conformational properties of the molecule that is being studied, the conformational ensemble that was sampled and optimized must be analyzed. The analysis may focus on global properties, attempting to characterize features such as overall flexibility or to identify common trends in the conformation set. Alternatively, it may be used to identify a smaller subset of characteristic low energy conformations, which may be used to direct future drug development efforts. It should be stressed that the different conformational analysis tools can be applied to any collection of molecular conformations. These... 

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