Modeling Macromolecular Complexes: A Journey Across Scales - Modeling in Computational Biology and Biomedicine - page 3

Fig. 1.1 Relevant objects in structural modeling vary in size from 1 A to 100 nm. ( a ) The radius
of an atom (nucleus and electron cloud) lies in the range 1-2 A, depending on the element and
chemical group to which it belongs. Each amino acid contributes four heavy atoms ( magenta )to
the backbone of the protein and has a variable side chain ( cyan )and blue ). Lysine is represented.
( b ) The backbone of lysozyme, a protein involving 162 amino-acids, colored by amino-acid type.
The diameter of the protein is circa 40 A, that is 4 nm. ( c ) With a size of circa 100 nm, the Nuclear
Pore Complex is the largest protein assembly known to date in eukaryotic cells
coordinates for a wide variety of sizes of structures, from small molecules to large
proteins. However, this technique has practical limits. Fewer than about 5 % of
the structures in the PDB correspond to non-redundant protein-protein or protein-
nucleic acid complexes [ 22 ]. An important factor here is the size of the complex.
Single-domain proteins are generally in the range of 1-2 nanometers (nm) [ 44 ]
(Fig. 1.1 b). Although structures of virus particles having a high degree of symmetry
have been solved, at 30 nm the ribosome is currently the largest asymmetric structure
solved by X-ray crystallography. Multidomain proteins, oligomers and complexes
can be much larger than this; the nuclear pore complex just mentioned measures
100 nm across [ 3 ](Fig. 1.1 c).
After X-ray crystallography, the importance of NMR spectroscopy to structural
determination of proteins is steadily increasing. Originating with the work of
K. Wuthrich, who was awarded the Nobel prize in Chemistry in 2002, successful
resolutions for proteins up to a few hundred residues are now commonplace.
Further, NMR data obtained for isolated proteins can be used in determining the
structures of complexes when only minor conformational changes occur upon
association, e.g., [ 49 ]. Protein-protein docking techniques [ 10 ] can be leveraged
in such determinations in much the same way that X-ray crystallography exploits
molecular replacement to resolve crystal structures of related proteins.
Another approach under active development is cryo-electron microscopy (Cry-
oEM) [ 27 ]. Structures as large as whole cells and as small as individual proteins can
be imaged with electrons, and with cryo techniques final resolutions on the order of
0.3 nm have been attained.
In single particle analysis, bombarding isolated samples with electrons yields
images corresponding to different viewpoints, and these can be combined into a 3D
model of the particle. In cryoEM tomography, a given sample is instead bombarded
at incremental degrees of rotation, from which a 3D model can also be reconstructed.