An approach is described for modelling the three-dimensional structure of a protein from the tertiary structures of several homologous proteins that have been determined by X-ray analysis. A method is developed for the simultaneous superposition of several protein molecules and for the calculation of an 'average structure' or 'framework'. Investigation of the convergence properties of this method, in the case of both weighted and unweighted least squares, demonstrates that both give a unique answer and the latter is robust for an homologous family of proteins. Multi-dimensional scaling is used to subgroup of the proteins with respect to structural homology. The framework calculated on the basis of the family of homologous proteins, or of an appropriate subgroup, is used to align fragments of the known protein structures of high sequence homology with the unknown. This alignment provides a basis for model building the tertiary structure. Different techniques for using the framework to model the mainchain of various globins and an immunoglobulin domain in the structurally conserved regions are investigated.
A systematic technique for protein modelling that is applicable to the design of drugs, peptide vaccines and novel proteins is described. Our approach is knowledge-based, depending on the structures of homologous or analogous proteins and more generally on a relational data base of protein three-dimensional structures. The procedure simultaneously aligns the known tertiary structures, selects fragments from the structurally conserved regions on the basis of sequence homology, aligns these with the 'average structure' or 'framework', builds on the loops selected from homologous proteins or a wider database, substitutes sidechains and energy minimises the resultant model. Applications to modelling an homologous structure, tissue plasminogen activator on the basis of another serine proteinase, and to modelling an analogous protein, HIV viral proteinase on the basis of aspartic proteinases, are described. The converse problem of ah initio design is also addressed: this involves the selection of an amino acid sequence to give a particular tertiary structure, in this case a symmetrical domain of two Greekkey motifs.The characterisation, production and engineering of new proteins by recombinant DNA technology has revolutionised approaches to the design of novel molecules of industrial, agricultural and clinical interest. However, systematic design requires a blueprint or plan which must describe the molecular architecture. For this reason protein crystallography and modelling have become central to rational approaches to : (a) modelling of protein receptors for drugs, herbicides and insecticides; (b) design of protein and peptide vaccines; (c) protein engineering of novel molecules.Unfortunately a detailed experimental definition of the three-dimensional structure of a protein is time-consuming and expensive, and its success is usually dependent on the production of well ordered crystals suitable for X-ray diffraction although proteins may be studied by two-dimensional NMR techniques. On the other hand, molecular modelling has been unsuccessful when approached using ab initio techniques of simulation and prediction, At Birkbeck we are developing a systematic approach to molecular modelling and design that is dependent on structural homology and analogy. It utilises a knowledge-based approach derived from structures defined by X-ray analysis. It seeks to develop a relational data base of protein three-dimensional structures and a set of rules that can be used to assemble amino acid sequences, secondary structures, loops, domains and tertiary structures of unknown proteins in an hierarchical manner [I, 21.The value of an homologous protein structure in modelling was first recognised by Browne et al. [3] in the construc- tion of a model of a-lactalbumin based on the threedimensional structure of lysozyme. Similar methods have been used to define structural features of a range of proteins including insulin-like growth factors, serine proteinases, renins and histocompatibility antigens (see [2] for review). However, these ...
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