The rates of reaction and reaction mechanisms in biological systems are the controlling factors in the metabolism and life cycles of all living organisms. Nevertheless, very little is known today about the details of these processes, particularly in more complicated life forms. For example, addition of certain metallic ions to an enzymic matrix can cause gross changes in enzymic activity (Brewer & Weber, 1966); just how these ions specifically enter into enzymic reactions is a subject of intense interest. The nature of the kinetics of bonding in nucleic acids is also the subject of much research (Eigen, 1967).

The sensitivity of biological systems to changes in environmental stimuli is connected with their regulatory properties. In order to achieve efficient control, these systems must respond to minute environmental variations by amplifying external stimuli to yield a significant response. To that end, biochemical systems have often evolved to a cascade organization in which the product of the nth reaction in a chain acts as a catalyst in subsequent transformations. The amplification properties of such cascades were first noticed in the process of blood clotting (MacFarlane, 1964, 1969) and visual excitation (Wald, 1965). Later on, a similar organization was noticed in hormonal control of metabolism (Bowness, 1964; Stadtman & Chock, 1977, 1978; Chock, Rhee & Stadtman, 1980).

Implementation and regulation of the molecular mechanisms underlying biological processes is dependent on direct interactions between biological molecules. These interactions are characterised by specific binding between at least one molecule and another, and for binding to occur the molecules must be able to come close enough to each other to make contact. One of the partners in the interaction is invariably a macromolecule (e.g. protein or DNA) or an assembly of large size, such as a lipid bilayer. The interaction may take place with the partners in solution, or with at least one attached to a biological surface (e.g. a membrane) or a very large structure such as a chromosome. Where the partners are part of a membrane or other large structure then there must be a mechanism, such as lateral diffusion in the plane of the membrane, that permits them to come together close enough for interaction.

Spectroscopic probes have become powerful tools in analysing the correlation between structure and function of biological macromolecules. Though these spectral methods cannot give as circumstantial information about the anatomy of a biological structure as, for example, X-ray diffraction they can provide information on physical properties at defined loci in a macromolecule which are not accessible by other techniques. Most important, spectroscopic studies have provided means to study the dynamics of structural changes and interactions in time domains spanning from nanoseconds and less up to infinite time.

Radiation damage is the main problem which prevents the determination of the structure of a single biological macromolecule at atomic resolution using any kind of microscopy. This is true whether neutrons, electrons or X-rays are used as the illumination. For neutrons, the cross-section for nuclear capture and the associatedenergy deposition and radiation damage could be reduced by using samples that are fully deuterated and 15N-labelled and by using fast neutrons, but single molecule biological microscopy is still not feasible. For naturally occurring biological material, electrons at present provide the most information for a given amount of radiation damage. Using phase contrast electron microscopy on biological molecules and macromolecular assemblies of ˜ 105 molecular weight and above, there is in theory enough information present in the image to allow determination of the position and orientation of individual particles: the application of averaging methods can then be used to provide an atomic resolution structure. The images of approximately 10000 particles are required. Below 105 molecular weight, some kind of crystal or other geometrically ordered aggregate is necessary to provide a sufficiently high combined molecular weight to allow for the alignment. In practice, the present quality of the best images still falls short of that attainable in theory and this means that a greater number of particles must be averaged and that the molecular weight limitation is somewhat larger than the predicted limit. For X-rays, the amount of damage per useful elastic scattering event is several hundred times greater than for electrons at all wavelengths and energies and therefore the requirements on specimen size and number of particles are correspondingly larger. Because of the lack of sufficiently bright neutron sources in the foreseeable future, electron microscopy in practice provides the greatest potential for immediate progress.

Gram-negative bacteria such as Escherichia coli (E. coli) and Salmonella typhimurium (S. typhimurium) have two layers of membranes in the cellular envelope – the cytoplasmic membrane and the outer membrane (Fig. I). Between these membranes is a periplasmic space in which there is a peptidoglycan layer that provides the cells with mechanical rigidity. In this periplasmic space, there are also a variety of hydrolases and binding proteins. The composition of the outer membrane is somewhat unusual. This membrane bilayer is asymmetric, having an inner (periplasmic) leaflet composed of phospholipids and an outer (extracellular) leaflet formed by lipopolysaccharide (LPS). Unlike phospholipids having two acyl chains, LPS has six or seven saturated fatty acid chains (see reviews, Lugtenberg & Van Alphen, 1983; Nikaido & Vaara, 1985; Nakae, 1986). The head groups of LPS have a strong affinity for divalent cations such as Ca2+, and given a sufficient concentration of these ions the outer membrane can form quite a formidable permeability barrier through this head group/salt bridge network (Nikaido & Vaara, 1985). The function of the outer membrane is to serve as a protective envelope against hostile environments such as those in the intestinal tract of animals where harmful and toxic substances - for example, bile salts and various enzymes - are often found. The outer membrane itself would be impermeable to most hydrophilic solutes were it not for the presence of membrane channels. The presence of a large number of pore-forming proteins provides both specific and nonspecific diffusion pathways across the outer membrane for solutes such as nutrients and waste products to diffuse into or out of the cell.

Theoretical methods of conformational analysis have been applied to the biopolymers with beneficial consequences for the elucidation of structure–function relationships in these molecules. The methodology of theoretical conformational analysis and the fruits of its application to the biopolymers, particularly the polypeptides, have been the subject of numerous reviews (Ramachandran & Sasisekharan, 1968; Scheraga, 1968; Venkatachalam & Ramachandran, 1969; Scheraga, 1971; Brant, 1972; Hopflnger, 1973). A critical evaluation of these techniques as applied to the polynucleotides has recently appeared (Olson, 1975 a, b).

Our scientific age is characterized by the extension of our dimensions to the extreme. Radiotelescopes are searching for echoes from the depth of the universe, while electronmicroscopes and X-ray diffractometers make the atomic and molecular structure of matter visible.

AUosteric proteins control and coordinate chemical events in the living cell. When Monod conceived that idea he said that he had discovered the second secret of life. The first was the structure of DNA. The theory as published by Monod et al. (1963) was concerned chiefly with cooperativity and feedback inhibition of enzymes, such as the inhibition of threonine deaminase, the first enzyme in the pathway of the synthesis of isoleucine, by isoleucine, and its activation by valine. Two years later the theory was formalized by Monod et al. (1965).

Lead is probably the oldest and most widely distributed environmental intoxicant, but unlike many of the synthetic agents which cause the greatest concern in industrial societies today, it occurs naturally at low levels in the environment and was present during evolutionary times. Galena (PbS), the most important lead-bearing mineral, is abundant and it is readily smelted. The metal is easily shaped and does not corrode and its compounds have found innumerable uses, particularly as pigments. This explains, in brief, why lead has had great economic importance since ancient times and why lead disease has plagued civilized societies for thousands of years and continues to be a serious concern to health authorities today. (Grandjean, 1975; Eisinger, 1977).

The application of magnetic resonance techniques to biological systems has permitted a detailed study of the nature of the active sites of many proteins that had not been possible previously. Among these is the whole class of iron—sulphur proteins which have been implicated as electron transport proteins in a variety of fundamental processes: photosynthesis, hydroxylation and nitrogen fixation to name but a few.

The single-iron proteins in this class, the rubredoxins, have been studied extensively by chemical, spectroscopic and X-ray crystallographic techniques (Lovenberg, 1973), and the active site is composed of a single iron atom bound in a distorted tetrahedron of cysteine sulphur ligands. The iron is high-spin ferric in the oxidized state and high-spin ferrous in the reduced state. This structure is shown in Fig. I (α).