There is a general trend in biochemistry toward more quantitative and sophisticated interpretations of experimental data. As a result, demand for accurate, complex, and elaborate calculation increases. Recent progress in computer technology, along with the synergy of increased need for complex biochemical models coupled with an improvement in software programs capable of meeting this need, has led to the birth of computational biochemistry (Bryce, 1992; Tsai, 2000).
Computational biochemistry can be considered as a second-generation interdisciplinary subject derived from the interaction between biochemistry and computer science (Figure 1.2). It is a discipline of computational sciences dealing with all of the three aspects of biochemistry, namely, structure, reaction, and information. Computational biochemistry is used when biochemical models are sufficiently well developed that they can be implemented to solve related problems with computers. It may encompass bioinformatics. Bioinformatics (Baxevanis and Ouellete, 1998; Higgins and Taylor, 2000; Letovsky, 1999; Misener and Krawetz, 2000) is information technology applied to the management and analysis of biological data with the aid of computers. Computational biochemistry then applies computer technology to solve biochemical problems, including sequence data, brought about by the wealth of information now becoming available. The two subjects are highly intertwined and extensively overlapped.
Computational biochemistry is an emerging field. The contribution of "computational" has contributed initially to its development; however, as the field broadens and grows in its importance, the involvement of "biochemistry" increases prominently. In its early stage, computational biochemistry has been exclusively the domain of those who are knowledgeable in programming. This hindered the appreciation of computational biochemistry in the early days. The wide availability of inexpensive microcomputers and application programs in biochemistry has helped to relieve these restrictions. It is now possible for biochemists to rely on existing software programs and Internet resources to appreciate computational biochemistry in biochemical research and biochemical curriculum (Tsai, 2000). Well-established
techniques have been reformulated to make more efficient use of the new computer technology. New and powerful algorithms have been successfully implemented.
Furthermore, it is becoming increasingly important that biochemists are exposed to databases and database management systems due to exponential increase in information of biochemical relevance. Visual modeling of biochemical structures and phenomena can provide a more intuitive understanding of the process being evaluated. Simulation of biochemical systems gives the biochemist control over the behavior of the model. Molecular modeling of biomolecules enables biochemists not only to predict and refine three-dimensional structures but also to correlate structures with their properties and functions.
The field has matured from the management and analysis of sequence data, albeit still the most important areas, into other areas of biochemistry. This text is an attempt to capture that spirit by introducing computational biochemistry from the biochemists' prospect. The material content deals primarily with the applications of computer technology to solve biochemical problems. The subject is relatively new and perhaps a brief description of the text may benefit the students.
After brief introduction to biostatistics, Chapter 2 focuses on the use of spreadsheet (Microsoft Excel) to analyze biochemical data, and of database (Microsoft Access) to organize and retrieve useful information. In the way, a conceptual introduction to desktop informatics is presented. Chapter 3 introduces Internet resources that will be utilized extensively throughout the book. Some important biochemical sites are listed. Molecular visualization is an important and effective method of chemical communication. Therefore, computer molecular graphics are treated in Chapter 4. Several drawing and graphics programs such as ISIS Draw, RasMol, Cn3D, and KineMage are described. Chapter 5 reviews biochemical compounds with an emphasis on their structural information and characterizations. Dynamic biochemistry is described in the next three chapters. Chapter 6 deals with ligand- receptor interaction and therefore receptor biochemistry including signal transductions. DynaFit, which permits free access for academic users, is employed to analyze interacting systems. Chapter 7 discusses quasi-equilibrium versus steady-state kinetics of enzyme reactions. Simplified derivations of kinetic equations as well as Cleland's nomenclature for enzyme kinetics are described. Leonora is used to evaluate kinetic parameters. Kinetic analysis of an isolated enzyme system is extended to metabolic pathways and simulation (using Gepasi) in Chapter 8. Topics on metabolic control analysis, secondary metabolism, and xenometabolism are presented in this chapter. The next two chapters split the subject of genomic analysis. Chapter 9 discusses acquisition (both experimental and computational) and analysis of nucleotide sequence data and recombinant DNA technology. The application of BioEdit is described here, though it can be used in Chapter 11 as well. Chapter 10 describes theory and practice of gene identifications. The following two chapters likewise share the subject of proteomic analysis. Chapter 11 deals with protein sequence acquisition and analysis. Chapter 12 is concerned with structural predictions from amino acid sequences. Internet resources are extensively used for genomic as well as proteomic analyses in Chapters 9 to 12. Since there are many outstanding Web sites that provide genomic and proteomic analyses, only few readily accessible sites are included. The phylogenetic analysis of nucleic acid and protein sequences is introduced in Chapter 13. The software package Phylip is used both locally and online. Chapter 14 describes general concepts of molecular modeling in biochemistry. The application of molecular mechanics in energy calculation, geometry optimization, and molecular dynamics are described. Chapter 15 discusses special aspect of molecular modeling as applied to protein structures. Freeware programs KineMage and Swiss-Pdb Viewer are used in conjunction with WWW resources. For a comprehensive modeling, two commercial modeling packages for PC (Chem3D and HyperChem) are described in Chapter 14 and they are also applicable in Chapter 15.
Each chapter is divided into four sections (except Chapter 1). From Chapters 5 to 15, biochemical principles are reviewed/introduced in the first section. The general topics covered in most introductory biochemistry texts are mentioned for the purpose of continuity. Some topics not discussed in general biochemistry are also introduced. References are provided so that the students may consult them for better understanding of these topics. The second section describes practices of the computational biochemistry. Some backgrounds to the application programs or Internet resources are presented. Descriptions of software algorithms are not the intent of this introductory text and mathematical formulas are kept to the minimum. The third section deals with the application programs and/or Internet resources to perform computations. Aside from economic reasons, the use of suitable PC-based freeware programs and WWW services have the distinct appeal of portability, so that the students are able to continue and complete their assignments after the regular workshop period. There has been no attempt to exhaustively search for the many outstanding software programs and Web sites or to provide in-depth coverage of the functionalities of the selected application programs or Web sites. The focus is on their uses to solve pertinent biochemical problems. By these initial exposures, it is hoped that interest in these programs or resources may serve as catalysts for the students to delve deeper into the full functionalities of these programs or resources. Arrows (—■) are used to indicate a series of operations; for example, Select — Secondary Structure — Helix indicates that from the Select menu, choose Secondary Structure Pop-up Submenu (or Command) and then go to Helix Tool (or Option). For submission of amino acid/nucleotide sequences to the WWW
servers for genomic/proteomic analyses, fasta format is generally preferred. The query sequence can be uploaded from the local file via browsing the directories/files or entering the path and the filename directly (e.g., [drive]:\[directory]\[file]). The copy-and-paste procedure (copying the sequence into the clipboard and pasting it onto the query box) is recommended for the online submission of the query sequence if the browser mechanism is unavailable. The requested executions by the Web servers appeared in capital letter (s), in italics or with underlines and are duplicated as they are on the Web pages. It is also helpful to know that the right mouse button is useful to bring up context sensitive commands that shortcut going to the menu bar for selection. Workshops in the last section are not merely exercises. They are designed to review familiar biochemical knowledge and to introduce some new biochemical concepts. Most of them are simple for a practical reason to minimize human and computer time.
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