xii + 234 pages. £11.95, $19.95 This short, but concise, description of the methods of molecular dynamics (MD) applied to biomacromolecules was prepared by two well-known pioneers, indeed amongst the initiators, of the application of the methods of statistical physics to molecular biology.The complexity of macromolecules in biological systems is a challenging problem. X-ray (and neutron) diffraction and NMR spectroscopy continue to furnish invaluable data on the fine structure of many proteins, nucleic acids and, more recently, model oligonucleotides, as well as their interactions with various ligands, e.g. enzyme-inhibitor and oligonucleotide-intercalator complexes.The data derived from X-ray structures have, in turn, made possible further refinements with the aid of theoretical approaches, such as the use of the Monte Carlo method to predict the hydration of a mini-helix of B-DNA, subsequently confirmed by a crystallographic study. But even these theoretical methods are limited to a description of the properties of molecules largely from a static viewpoint. The concept that structural fluctuations occur in macromolecules, and that these are intimately related to biological function, is by no means new, and is reflected in frequent references to protein 'mobility' and the 'breathing' of a double helix.What is now novel and fascinating is the extension of the theoretical methods to include time-dependence, e.g. changes in conformation accompanying ligand-receptor interactions, in other words the dynamics of the molecular processes leading to an 'induced fit', also referred to as 'docking'. Such calculations by means of molecular dynamics are based on a combination of methods of classical molecular mechanics and statistical physics for describing the fluctuations of many-body systems.The volume presents a reasonably good description of the fundamental structures of proteins and nucleic acids, and the biochemical processes they participate in. This is followed by an outline of the various techniques of computer simulation and statistical mechanics employed in the calculations. Extensive descriptions are presented of the type of information gleaned during the past 10 years with the use of MD methods to study biomacromolecules and, in some instances, comparisons with experimental results, such as those obtained by means of dynamic NMR spectroscopy.A rather brief section describes potential practical future developments in terms of computing techniques and the methodology employed, including possible extension of the time scale of the processes investigated from subnanoseconds to microseconds, or even longer. Highly relevant to this are current new developments in the technique of millisecond crystallography (Laue diffraction) to follow experimentally the changes in conformation of a protein during a reaction (see Ringe, D. (1987) Nature, Sept. 10, page 102, and references cited).

Apolipoprotein A-I (apoA-I) is the principal protein of high density lipoprotein particles (HDL). ApoA-I contains a globular N-terminal domain (residues 1-43) and a lipid-binding C-terminal domain (residues 44 -243).Here we propose a detailed model for the smallest discoidal HDL, consisting of two apoA-I molecules wrapped beltwise around a small patch of bilayer containing 160 lipid molecules. The C-terminal domain of each monomer is ringlike, a curved, planar amphipathic ␣ helix with an average of 3.67 residues per turn, and with the hydrophobic surface curved toward the lipids. We have explored all possible geometries for forming the dimer of stacked rings, subject to the hypothesis that the optimal geometry will maximize intermolecular salt bridge interactions. The resulting model is an antiparallel arrangement with an alignment matching that of the (nonplanar) crystal structure of lipid-free apoA-I. Apolipoprotein (apo)1 A-I is the major protein component of the antiatherogenic high density lipoproteins (HDL). There are eight 22-mer and two 11-mer tandem amino acid sequence repeats, each with the periodicity of an amphipathic ␣ helix (1, 2), often punctuated by prolines, encoded in exon 4 of the apoA-I gene (residues 44 -241).ApoA-I is an integral component of both spheroidal circulating HDL particles and the geometrically simpler discoidal (hockey puck-like) nascent HDL particles. The better characterized discs are small unilamellar bilayers, containing approximately 160 molecules of phospholipid, surrounded by two apoA-I monomers (3-5). Two general models have been proposed for apoA-I on the disc rim: (i) two molecules of apoA-I form a pair of continuous amphipathic ␣ helices parallel to the plane of the disc (the "double belt" model) (3, 6 -8); (ii) the 22-mer amphipathic ␣ helical repeats of apoA-I form tandem antiparallel helices perpendicular to the plane of the disc (the "picket-fence" model) (9, 10). Although total reflectance Fourier-transform infrared spectroscopy studies of discoidal HDL have been interpreted as supportive of the picket-fence model (11) because the samples were dried prior to study, these conclusions are open to question. A recent study of discoidal HDL using polarized internal reflection infrared spectroscopy under native conditions unambiguously supports the belt model (12).In the recently published x-ray structure, residues 44 -243 of apoA-I form an almost continuous amphipathic ␣ helix, and the authors suggest that these results support the double belt model for discoidal HDL (7). Because lipid has a profound effect on the conformation and orientation of protein that interacts with it (13, 14), we hypothesized that if the double belt model was correct, the geometry of a planar bilayer disc should place constraints upon lipid-associated apoA-I such that the hydrophobic face of a continuous amphipathic ␣ helix would: a) be confined to a plane and b) form the inside of a continuous amphipathic ␣ helical torus. (15) were modified to create a PITCH ϭ x option to allow unlimited var...

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