How useful are the modeled protein structures?
Wish you all “A Very Happy and Prosperous New Year!!!”
Since my last post, discussion on individual threads was required, in this post I will discuss on modeled protein structures.
Why model protein structures?
To understanding the biological function of proteins including their interactions with other proteins, ligands, substrates and inhibitors, it is necessary to determine their 3D structure. Classical methods of structure determination take massive time and money.
Thus, computational methods for predicting the protein structure form the sequence, like Ab-initio, threading, comparative modeling, become increasingly important.
How accurate are modeled protein structures?
For reasons like huge number of conformations of protein structures and incomplete understanding about physical stability of protein structures; the chances of errors in modeled structures are high. The extent of errors inherited in the model may be different in different regions, like the non-conserved surface loops are expected to be the least reliable parts of a protein structure may deviate markedly from experimentally determined control structure.
Modeled helices and strands are ideally straight, while bends, due to many factors steric interaction between side chains or interaction with solvent molecules, are often found in the secondary structures of proteins. On the contrary, such a tricky assignment of secondary structure could produce large bends in the protein structure, which can be analyzed by visual inspection.
Optimizing local atomic geometry of the structure, deviation from global topology is expected and when a small number of discrete states are used to represent a protein structure, the structure is necessarily distorted. Although small in nature the distortion effects can be cumulative, small distortions in a larger target can lead to substantial structural changes.
Use of modeled protein structures?
Inclusion of predicted protein structures with local structural distortions in the screening process may yield much lower enrichment of known actives, especially for structural distortions present near the binding site, resulting in significant drop-off in the ability to recognize ligands. Interpretation of the in-vivo expression profiles of proteins on the basis of such a model may be misleading.
Identifying the sources and magnitude of errors/variations in predicting biological profiles for small molecules could prove critical in cases where modeled proteins are the only solution.