Protein Folding and Beyond

Yong Duan, Stephen C. Harvey and Peter A. Kollman 

How do proteins fold into their native structures To study the mechanism of protein folding is to seek an answer to this question. The astronomically large number of possible conformations suggests that proteins use some sort of directed mechanisms to fold. Under evolutionary pressure, these mechanisms have been refined such that proteins can fold reasonably quickly to well-defined functionally useful structures. We will review briefly the history of protein folding studies and discuss the theoretical studies in more detail. We will concentrate on recent developments and give a brief perspective of the future. 

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Discussion of the field of conformational analysis and protein folding is beyond the scope of this section. Nevertheless, the concept that the most potent drugs mimic the three-dimensional ( biologically active ) structure of the native peptide bound to its receptor became an important driving force in the field of peptide chemistry. The stabilization of this structure would result in increased potency and more efficacious pharmaceuticals. 

Importantly, such strategy could be adapted for use well beyond the actual scope of protein folding and might be useful where other kinds of template are available. 

G. Ramachandran and T. Schlick. Beyond optimization Simulating the dynamics of supercoiled DNA by a macroscopic model. In P. M. Pardalos, D. Shal-loway, and G. Xue, editors. Global Minimization of Nonconvex Energy Functions Molecular Conformation and Protein Folding, volume 23 of DIM ACS Series in Discrete Mathematics and Theoretical Computer Science, pages 215-231, Providence, Rhode Island, 1996. American Mathematical Society. 

Forrer, P., Jung, S., and Pluckthun, A. (1999). Beyond binding using phage display to select for structure, folding and enzymatic activity in proteins. Gun. Opin. Biotechnol. 9, 514-520. 

Molecular models can considerably impact the chemical process industry. Obviously, numerous problems fall beyond the realm of conventional molecular simulation (see the example above on zeolitic membranes). Examples include dynamics of protein folding, diffusion through microporous membranes and human cells, formation of quantum dots in heteroepitaxial growth of semiconductors, and pattern formation on catalyst surfaces. 

Beyond protein folding, the discovery of peptidyl prolyl isomerases (PPIases) and related proteins has opened the way to novel concepts in biology the notion of chaperone-assisted receptor binding is an emerging field of research which sheds light on receptor function and protein-protein interactions. The recent discovery of a secondary amide peptide bond cis-trans isomerase (APIase) heralds new advances in this field. 

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