What is the rationale for yet another biochemistry book? What do I mean by chemical logic?
Many who have taught chemistry (general, organic, biochemistry) from a traditional book invariably believe that the book would be better if it had a different organization or different conceptual framework. Few can truly cover the extent of information found in these encyclopedic tomes. All textbooks within a specialty area of chemistry have the same topic orders as well.
Biochemistry Online: An Approach Based on Chemical Logic was written, in part, to deal with issues of topic order and conceptual framework. The rationales for adoption of this framework for the teaching of the first semester of a biochemistry course have been published in the manuscript below.
A PowerPoint Slide presentation and a summary of the paper follow.
Powerpoint Slide Show: Biochemistry Based on Chemical Logic
Summary: The chosen topic order should create a coherent and sequential understanding of biochemistry, not a fragmented one without logical connections among topics. Textbook authors offer assistance in addressing these concerns in two ways. They implicitly suggest an order of presentation by how chapters are arranged and they offer philosophical interpretations to describe biochemistry. Scrutiny of the philosophy statements ("Chemistry is the logic of biological phenomena."; "..common molecular patterns and principles underlie the diverse expression of life."' and ..."molecular logic of life.") and chapter organization of textbooks reveals commonalties among textbooks.
This consensus, however, does not lead to a linkage between philosophy and content. The present organization of texts is not derived from the central dogma of biology, since in most books protein structure precedes significant discussions of nucleic acid structure/function. Rather, it seems to reflect evolving tradition based on historical trends in biochemistry research, as evidenced by chapter organization of major biochemistry texts, starting from the 1935 edition of Harrow's Textbook of Biochemistry (4,5). Early texts commenced with discussions of carbohydrate chemistry, followed by lipids and then proteins. Texts from the late sixties onward invariably led with protein chemistry, and deferred carbohydrate and chemistry until much later (5-7).
Although modern authors speak of a "chemical logic", it is not evident in textbook organization. Biochemistry Online was written to present biochemistry in the framework of a higher order organizing principle, based in chemical logic and understanding, from which topics and order of presentation derive. New topics can then be introduced in a fashion which the students perceive not as random but as a logical extension based on a developing understanding.
Throughout the course, three major recurring chemical principles become evident: structure determines function/activity; binding reactions initiate all biological events; and chemical principles, such as dynamic equilibria (mass action), and reaction kinetics and mechanisms, derived from the study of small molecules, can be applied to the behavior of macromolecules. The order of the topics is based on evolving chemical logic.
Topic 1 - Lipid Structure: The first topic is lipid and lipid aggregate structure/function, instead of amino acids and proteins, as is typically presented. Prior to taking a biochemistry course, students have had little significant exposure to the chemical properties of macromolecules, so beginning with the study of small molecules makes sense. Since most lipids are amphiphiles, their structural diversity can be simplified by considering them as simple structures with spatially distinct polar and nonpolar ends. Single chain and double chain amphiphiles aggregate in a thermodynamically spontaneous manner to form micelle and bilayer structures, respectively, with the nonpolar parts sequestered from water and associated with themselves, and the polar parts solvent-accessible. This simple model introduces students to the notion that structure mediates properties, to the important concept of intermolecular forces, and to the thermodynamics of the hydrophobic effect, all critical elements ultimately required to understand the much more complicated topic of protein folding and stability. The concepts of mass conservation, dynamic equilibria and kinetics, and chemical potential, are used to understand how aggregation at equilibrium depends on amphiphile concentration. Lipids serve as useful models to introduce stereochemistry and prochirality as well. Likewise, it is easier to understand how torsion angle changes in the aliphatic side chains of phospholipid molecule alter acyl chain packing, than it is to understand the complexities of a Ramachandran plot. From a chemical perspective, it is more logical to introduce the spontaneous self assembly of small amphiphilic molecules into large multi-molecular aggregates than to start with the physiochemical properties of twenty different amino acid which vary in size and hydrophobicity and proceed to the complexities of intramolecular protein folding reactions.
Topic 2 - Protein Structure: The understandings derived from the study of lipids can then be applied to the more complex subject of intramolecular protein folding reactions and protein stability. A more expanded and modern view of the hydrophobic effect and associated heat capacity change is presented, along with the denaturing effect of chain conformational entropy. The role of the hydrophobic effect and H-bonds in protein stability are extrapolated from the behavior of benzene in water and thermodynamic cycles involving the transfer of N-methylacetamide from water to a nonpolar solvent, and from mutational studies. Dynamic and linked equilibria considerations, along with reaction kinetics, are used to describe the varying effects of denaturing (urea, guanidinium chloride) and stabilizing (ammonium sulfate, glycerol) solutes on protein stability, as well as the competing processes of protein folding and aggregation in vitro and in vivo.
Topic 3 - Nuclei Acid and Carbohydrate Structure: The same principles which determine protein structure/function can be applied to the study of the structure and stability of nucleic acids, complex carbohydrates, and glycoproteins.
Topic 4 - Binding: Function now necessarily follows. Since all biological events are initiated by binding, a purely physical process, the logic of chemistry suggests it should be studied next. Indeed, in most textbooks, introductory chapters on protein function focus on the binding of dioxygen, a simple ligand, to myoglobin and hemoglobin. Macromolecule-drug interactions, as well as cell-cell adhesion can be discussed as additional relevant examples. The control of gene expression, a topic of preeminent importance to modern biologists, can be discussed from the logic of chemistry as an essential outcome of the binding of transcription factors and appropriate enzymes to each other and DNA in the active transcription complex. It is particularly important to stress how equilibrium and mass conservation principles, along with reaction kinetics, effectively determine the concentration-dependent behavior of all molecules, including the processes of binding and spontaneous structure formation.
Topic 5 - Binding and Transport: Binding is an antecedent to the expression of biological activity. The simplest expression of activity which involves a simple physical, non covalent, process is binding and transport of solute molecules across a biological membrane. Mathematical analyses of the flux of solute across a membrane catalyzed by a transport protein involves the same assumptions (rapid equilibrium/steady state binding) and leads to the same equations (hyperbolic dependence of flux with outer solute concentration, effect of competitive inhibitors) as when Michaelis-Menten enzyme kinetics mechanisms are modeled.
Topic 6 - Binding and Kinetics: The study of enzyme kinetics follows as a logical extension of the expression of molecular function involving the addition of a more complex step, namely a chemical transformation. Through the study of enzyme kinetics, students learn how to obtain a low resolution understanding of the structure/activity of enzymes and of their chemical mechanisms.
Topic 7 - Binding and Chemical Transformations: Next, the detailed mechanism of specific enzymes whose structures are known is discussed. Preceding this, the basis for catalysis by small molecules is discussed. Following the chemical logic that the properties of macromolecules can be inferred from small molecules, students learn, that with respect to catalysis, enzymes are "not different, just better", than small molecule catalyst, as previously described by Jeremy Knowles (1).
Topic 8 - Energy and Signal Transduction: The final sequence involves specific examples of how enzymes can transduce both energy and information signals into useable outputs. Energy transduction, involving the conversion of light, electrochemical gradients, or chemical energy, into phosphoanhydride bonds, is discussed. Special attention is paid to biological oxidation reactions. Several questions are introduced to provoke discussion and challenge students' knowledge of oxidation reactions. Students propose reasons to explain the fact that oxidation reactions of organic molecules using dioxygen are thermodynamically but not kinetically favored, as well as to explain the need for different types of biological oxidizing agents for energy transduction. Signal transduction at the cell membrane serves as an excellent capstone area of study since it incorporates ideas from each sequence.
1. Knowles, J. Nature. 350,121-124 (1991)