Structure, three-dimensional protein-folding pathways

Invent computer methods to predict the three-dimensional folded structure of a protein—and the pathway by which folding occurs—from its amino acid sequence, so information from the human genome can be translated into the encoded protein structures. 

Proteins spontaneously fold into their native conformation, with the primary structure of the protein dictating its three-dimensional structure. Protein folding is driven primarily by hydrophobic forces and proceeds through an ordered set of pathways. Accessory proteins, including protein disulfide isomerases, peptidyl prolyl cis-trans isomerases, and molecular chaperones, assist proteins to fold correctly in the cell. 

The biological activity of proteins generally depends on a unique three-dimensional conformation, which in turn is inherently linked to its primary sequence. Protein folding, the conversion of the translated polypeptide chain into the native state of a protein, is the critical link between gene sequence and three-dimensional structure. Mechanistically, folding is believed to proceed through a predetermined and ordered pathway, either via kinetic intermediates or by direct transition from the unfolded to the native state [99]. In both cases, local and non-local interactions alike stabilize transient structures along the pathway and funnel the intermediates towards the native state. 

These observations led to the study of what has now become a field of wide interest—the pathway(s) in the folding process. This volume of Advances in Protein Chemistry contains discussions of a number of ancillary catalytic systems that may help us understand the great rapidity and steric specificity exhibited during the transition from unidimensional chaos to three-dimensional, functional structure. 

Nucleic acids can play roles farbeyond merely harbouring the coding information for proteins. Single-stranded nucleic acids can fold into intricate structures capable of molecular recognition and even catalysis. Three-dimensional structures are specified by the primary structure, namely the deoxynucleotide (or nucleotide, for RNA) sequence (5 - 3, by analogy to the situation in which the amino-acid residue sequence determines the three-dimensional structures of polypeptides. In nature, transfer RNAs (tRNAs) use their three-dimensional shape for molecular recognition, while some ribosomal RNAs (rRNAs) are able to catalyse crucial steps even within the protein synthetic pathways themselves. 

The basic thesis has served as the stimulus for a large number of studies directed towards the prediction of protein three-dimensional structures from their amino-acid sequences alone. Implicit in most of the predictive methods investigated are two concepts (i) that there is in the protein the clearly-observed hierarchical structural arrangement (primary structure - secondary structure - secondary aggregates or super-secondary structure - domains - total structure) which has already been discussed in the previous section and (ii) that the folding process of a random chain to give the stable native structure is kinetically-controlled and that it proceeds via a characteristic and predictable pathway. This pathway is visualized as requiring nucleation at various sites around which the subsequent... 

In spite of their differences, all of the mechanisms mentioned above assume that the information needed to produce the native structure is entirely encoded in the amino acid sequence, so that the form of the initial structure is immaterial and all downhill pathways in free energy will eventually lead to the same final three dimensional structure. On the other hand, in a multifunnel free energy landscape, a kinetic process must involve a specific pathway, as already noted by Levinthal. What is a specific pathway In physical terms, it is a dynamical process in which a well defined sequence of forces is applied to the protein atoms, making the protein follow a given trajectory. But in a dynamical process, the evolution of the system depends, not only on the forces applied, but also on the initial condition. Thus, in a kinetic mechanism for folding the initial structure cannot be arbitrary and its form is instead very important for the final result. Therefore, a first consequence of a multi-fuimel free energy landscape, and of a kinetic mechanism for folding, is that the initial conformation, that is, the conformation... 

A. Kolinski, A. Godzik, and J. Skolnick, A general method for the prediction of the three dimensional structure and folding pathway of globular proteins Application to designed helical proteins. J. Chem. Phys. 98, 7420-7433 (1993). 

The general problems on proteins that can be in principle solved via MM simulations are (1) the construction of three-dimensional structure of the macromolecule and prediction of the pathways of protein folding using restricted experimental data (ideally, the primary structure only) (2) the refinement of experimental structure (X-ray diffraction patterns usually do not supply us with information sufficient for precise atom coordinate assignment). The whole problem of the proteins functioning as enzymes cannot be solved via MM only, as chemical reactions are beyond the MM approach, quantum mechanics considerations are indispensable. Nevertheless, the MM approach is useful for the problems of enzyme-substrate complex formation and of molecular recognition, which are crucial for protein functions. 

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