Structure computational aspects

Hall LH (1990) In Rouvray DH (ed) Computational aspects of molecular connectivity and its role in structure-property modeling computational chemical graph theory. Nova Science Publishers, New York, NY, chap 8, p 202... 

The Patai Series publishes comprehensive reviews on all aspects of specific functional groups. Each volume contains outstanding surveys on theoretical and computational aspects, NMR, MS, other spectroscopical methods and analytical chemistry, structural aspects, thermochemistry, photochemistry, synthetic approaches and strategies, synthetic uses and applications in chemical and pharmaceutical industries, biological, biochemical and environmental aspects. 

The Human Genome Project went three-dimensional in late 2000. Structural genomics efforts will determine the structures of thousands of new proteins over the next decade. These initiatives seek to streamline and automate every experimental and computational aspect of the structural determination pipeline, with most of the steps involved covered in previous chapters of this volume. At the end of the pipeline, an atomic model is built and iteratively refined to best fit the observed data. The final atomic model, after careful analysis, is deposited in the Protein Data Bank, or PDB (Berman et ah, 2000). About 25,000 unique protein sequences are currently in the PDB. High-throughput and conventional methods will dramatically increase this number and it is crucial that these new structures be of the highest quality (Chandonia and Brenner, 2006). 

In recent years, the ground-state and excited-state electronic structure of nucleobases and short oligonucleotides has become much clearer. Because other chapters in this book review the experimental, theoretical and computational aspects of nucleobase and oligonucleotide electronic states, only a very brief review will be given here. 

Computational aspects of structure determination of biological macromolecules. This has important implications about the expected quality of the final results. 

Hall, L.H. (1990). Computational Aspects of Molecular Connectivity and its Role in Structure-Property Modeling. In Computational Chemical Graph Theory (Rouvray, D.H., ed.). Nova Press, New York (NY), pp. 202-233. 

This chapter is structured as follows In Sect. 6.2, a basic introduction to molecular refinement is presented, stressing particularly relevant aspects. Section 6.3 reviews the recent work by Falklof et al., describing how the 2 x 2 x 2 supercell for the lysozyme structure was obtained. Section 6.4 reviews some modern advances in DFT, focusing on dispersion-corrected DFT, while Sect. 6.5 describes the effects of DFT optimization of atomic coordinates on the agreement between observed and calculated X-ray structure factors. The aim is to determine an optimal electronic-structure computational procedure for quantum protein refinement, and we consider only the effects of minor local perturbations to the existing protein model rather than those that would be produced by allowing full protein refinement. 

The Hansch method, known as quantitative structure-activity relationships (QSAR), has evolved to embrace a variety of techniques. A glance at the recently published proceedings of the European QSAR Conference [1] shows how much of an impact the methods of pharmacophore discovery have on the computational aspects of medicinal chemistry. Indeed, looking up publications that cite various pharmacophore discovery methods papers, it is surprising to see that the total has rapidly accelerated in the past few years, demanding that a review such as this sort through hundreds of papers. 

Before discussing in detail the numerical results of our computational work, we describe the theoretical and computational context of the present calculations apart from deficiencies of models employed in the analysis of experimental data, we must be aware of the limitations of both theoretical models and the computational aspects. Regarding theory, even a single helium atom is unpredictable [14] purely mathematically from an initial point of two electrons, two neutrons and two protons. Accepting a narrower point of view neglecting internal nuclear structure, we have applied for our purpose well established software, specifically Dalton in a recent release 2.0 [9], that implements numerical calculations to solve approximately Schrodinger s temporally independent equation, thus involving wave mechanics rather than quantum... 

As has been discussed in the introduction, the possibility of a relation between parity violating energy differences and the biochemical homochirality observed on earth has been noted by Yamagata [11] a decade after the discovery of parity violation in nuclear physics. Various different kinetic mechanisms have been proposed which could possibly amplify the tiny energy difference between enantiomeric structures to result in an almost exclusive chiral bias on a time scale relevant for the biochemical evolution. This aspect as well as other hypotheses regarding the origin of the biochemical homochirality have been discussed and reviewed multiple times (see for instance [33,37-39,190-193] and literature cited therein) so that we can concentrate here on the computational aspects of molecular parity violating effects in biochemical systems. 

One need look no further than some of the recent reviews in peptide mimetic chemistry - to see the substantial impact of computational chemistry on this field. For example, the 1993 Symposium-in-Print edition of Tetrahedron, entitled Peptide Secondary Structure Mimetics, contains 19 articles by practitioners involved in peptide mimetic design. The majority of these articles include references to the use of some form of computational chemistry in the research effort. In addition, as a further indication of the commercial interest, even a recent patent dealt with the computational aspects of peptidomimetic design. 

A common mantra throughout this chapter is that diagrams are essential. A difficulty is that you generally need more than one diagram (view) to appreciate a three-dimensional (3D) structure. Computer programs can make the 3D aspects much more apparent. 

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