Protein modeling Chemical Computing Group

Diversity of protein structure and function is enhanced by the different chemical functional groups seen in the 20 common amino acids. This variety, however, complicates the development of empirical force field parameters for proteins. For simplicity we will simply list a number of the model compounds used for the different amino acids. This is presented in Table 1. The selection of appropriate model compounds is based on a balance between the size of the compound and the available target data. For example, a large number of gas and condensed phase data are available for methanol however, sole use of that compound for the sidechains of serine or threonine avoids accurate tests of parameters associated with the covalent connection of the sidechain to the backbone. This is overcome by the use of larger compounds such as ethanol and isopropanol. Increases in computational resources will allow for ab initio calculations on larger model compounds. However, as discussed in the previous section, care... 

Figure 22 Introducing normative prosthetic group into metalloproteins. (a) by chemical modification of heme propionate. (Reprinted with permission fi-om Ref. 25. 2002 the American Chemical Society) (b) by noncovalent addition strategy. The crystal stmcture of the Fe (3,3-Me2-salophen) incorporated into AlalTGlaMb. (Reprinted with permission from Ref 287. 2004 the American Chemical Society) (c) by a single attachment strategy. The computer model of adipoc)4e lipid binding protein-phenanthroline complex. (Reprinted with permission from Ref. 291. 1997 the American Chemical Society) (d) by a dual covalent attachment strategy. The computer model of Mb(L72C/Y 103C) with a Mn "-Salen complex covalently attached at two-points and overlayed with heme. (Reprinted with permission from Ref 288. 2004 the American Chemical Society)...

Experimentally determined electron density maps are never perfect because of defects in the data and phases, and as a consequence even the best of models will have errors in atomic positions, errors in dihedral angles, improper rotomers for side chains, or unacceptable contacts between atoms or chemical groups. When the quality of an electron density map is marginal or poor, serious errors in the model may occur, or the model may be fundamentally wrong. Even when the electron density map is good, and the model for most practical purposes correct, errors remain. The initial model for a protein will, in general, have rms errors in atomic positions of 1A or more, and an R factor computed from the model (with the exception perhaps of models obtained from molecular replacement) on the order of 0.50, an often discouraging result. 

Most quantum chemical modelling studies deal with active site chemistry. That is, the calculations do not really focus on how substrates and products get to and from the active site. Rather, they concentrate on the sequence of events following the arrival of substrate in the active site pocket and seek to uncover the mechanism of conversion of substrate to one or more intermediates and/or product. The obvious reason for such an approach is the assumption that the vast bulk of the protein molecule can be ignored but raises the thorny issue of whether this is a valid assumption. In practical terms, it is not possible (and arguably not desirable) to treat the entire protein quantum mechanically. Moreover, since one of the main roles of the protein is substrate selection and delivery to the active site, and since the computer modeller has explicit control over this feature, one might conclude that there is no need to consider the bulk of the protein molecule. However, the protein backbone may exert a structural influence on the active site—the entatic state [34]—while the groups around the active site produce an electrostatic field different from the in vacuo state which is the default domain of quantum chemistry. In summary, it is obviously critically important to develop a reasonable chemical model of the active site if any conclusions drawn from the calculations are to be believed. 

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