Anatomy of protein structures: Visualizing how a one-dimensional protein chain folds into a three-dimensional shape

Abstract

Here, we depict the anatomy of protein structures in terms of the protein folding process. Via an iterative, top-down dissecting procedure, tertiary structures are spliced down to reveal their anatomy: first, to produce domains (defined by visual three-dimensional inspection criteria); then, hydrophobic folding units (HFU); and, at the end of a multilevel process, a set of building blocks. The resulting anatomy tree organization not only clearly depicts the organization of a one-dimensional polypeptide chain in three-dimensional space but also straightforwardly describes the most likely folding pathway(s). Comparison of the tree with the formation of the hydrophobic folding units through combinatorial assembly of the building blocks illustrates how the chain folds in a sequential or a complex folding pathway. Further, the tree points to the kinetics of the folding, whether the chain is a fast or a slow folder, and the probability of misfolding. Our ability to successfully dissect the protein into an anatomy tree illustrates that protein folding is a hierarchical process and further validates a building blocks protein folding model. protein folding ͉ anatomy ͉ hydrophobic folding unit ͉ building block H ow a one-dimensional (1D) polypeptide chain folds into a three-dimensional (3D) entity is a fascinating problem. Despite our increasing knowledge, and the considerable progress made in the improvement of the methodology for the prediction of a protein 3D structure from its sequence (1), the protein folding problem still presents a major hurdle. Part of the reason why the folding problem remains so difficult derives from a lack of a folding model that enables visualizing how a 1D protein chain folds into its 3D native state. To fill this gap, we have devised, based on the building block folding model (2, 3), a procedure for progressively dissecting native protein structures to reveal their anatomy. Here we show how, based on their structural anatomy, we may visualize their dynamic folding pathways.

Molecular dynamics simulation of Escherichia coli dihydrofolate reductase and its protein fragments: Relative stabilities in experiment and simulations

“…8. Contact maps calculated for (a) the X-ray dihydrofolate reductase (DHFR) structure and the structures at the end of the simulation using (b) the three AS-DHFR fragments based on Gegg's cutting (Gegg et al 1997), and (c) the three DHFR fragments based on the Tsai et al (2000) cutting into building block algorithm. Each of the fragments is designated by the area enclosed by the rectangular box.…”

“…The notation of the secondary structure used in this study is based on the Protein Data Bank (PDB; Bernstein et al 1977) Ala and Ser, respectively (in CPK rendering). The molecular dissection is based on the Gegg et al (1997) study and on the Tsai et al (2000) dissection algorithm (the cutting result can be viewed at our web site at http://protein3d.ncifcrf.gov/tsai/ anatomy.html. Six of the seven folded protein fragments used in the study are shown in red, green, and yellow in the two structures.…”

“…The procedure is reapplied to each of the building blocks at each level of the protein cutting until no further cutting is possible. [For details of the protein cutting into building blocks algorithm, see Tsai et al (2000) or visit our Web site at http://protein3d.ncifcrf.gov/tsai/anatomy.html.] Applying this procedure to the native DHFR structure, the second level of dissection generates fragments 5-35, 35-103, and 104-159 (see Fig.…”

“…A basic unit from which a fold is constructed, that is, a hydrophobic folding unit (HFU), may be viewed as an outcome of a combinatorial assembly of microdomains, foldons, or building block folding elements (Karplus and Weaver 1994;Panchenko et al 1996Panchenko et al , 1997Tsai et al 1999aTsai et al , 2000. The HFUs in turn associate to create intramolecular domains, which subsequently assemble to build either an intramolecular multidomain protein fold or an intermolecular quaternary structure.…”

Recent developments in structural proteomics for protein structure determination

“…Another approach to simplify the protein-folding problem is the building block folding model, in which protein fragments are produced either experimentally [101,102] or computationally [103][104][105][106]. Whether these fragments can form independent folding entities is further determined [107].…”