The Construction of New Proteins and Enzymes‐a Prospect for the Future?

Abstract

Dedicated to Professor Paul J. FIory on the occasion of his 75th birthday Only a vanishingly small proportion of the almost infinite number of possible proteins occur in nature. Can this remaining potential of structural and functional diversity be used in the construction of new proteins? Is a "second evolution" of proteins and enzymes about to occur? These questions have suddenly become of interest because the recombinant DNA technique allows the synthesis of any given amino acid sequence. Examples of enzyme models demonstrate clearly that the unusual catalytic properties of enzymes are associated with the presence of a specifically folded polypeptide chain which has a complex three-dimensional form. The critical hurdle in the path of artificial proteins is thus the design of amino acid sequences which are able to fold into tertiary structures.-Recent studies on the topology and the mechanism of folding have provided considerable insight into the occurrence of, and the rules governing the three-dimensional architecture of proteins. Secondary structures apparently play a key role in the folding process; helices and "b-structures" act as nucleation centers directing folding and account for the surprisingly small number of different folding topologies. The problem of secondary structure formation can be investigated directly by means of conformational studies on model peptides. Oligopeptides with tailormade physicochemical, structural and conformational properties can already be designed. The theoretical and experimental basis for the construction of polypeptides with stable tertiary structures is therefore established. The path to macromolecules with an immense variety of novel properties lays before us.

Monte Carlo simulation of equilibrium globular protein folding: alpha-helical bundles with long loops.

“…Thus, to a good approximation the model protein undergoes the all-or-none transition. This is the same kind of transition as is observed in real proteins (5,38,39). Finally, at a temperature T* = 0.5, the chain is folded into the unique native state and has Vnat = 21.…”

“…The problem of predicting the tertiary structure of a globular protein, given the primary sequence of amino acid residues that constitute it, is one of the most important and most exciting problems in biochemistry, and many attempts recently have been made to solve this problem (1)(2)(3)(4)(5)(6)(7). While a wealth of information on the three-dimensional structure of globular proteins exists (5) remarkably little is known about the essential factors governing the folding of proteins to their native conformation.…”

“…While a wealth of information on the three-dimensional structure of globular proteins exists (5) remarkably little is known about the essential factors governing the folding of proteins to their native conformation. The main questions one confronts are: What is the relative role of long-range vs. short-range interactions in determining the native state (8)(9)(10)?…”

Switch-Peptides as Folding Precursors in Self-Assembling Peptides and Amyloid Fibrillogenesis

“…Based on the close relationship between the onset of secondary structure and physico-chemical properties of a growing peptide chain, notably the dramatic decrease in solubility due to self-association and b-sheet formation, [1][2][3][4][5][6]23 the idea of conformationally dissecting the regular amide backbone by insertion of a switch-element S at appropriate sites (resulting in sequences of chain length below the critical length (n c , b) for bsheet formation) has emerged ( Figure 1a). As we will show here, switch-elements can be composed of depsipeptide (also called O-peptide or O-acyl isopeptide) units and/or pseudoprolines (CPro).…”

“…[1][2][3] In this context, the design and investigation of model peptides exhibiting a high propensity for secondary and tertiary…”