Atomic Level Protein Flexibility Measure
DesertSci’s Scorpion software quantitively analyses molecular interaction networks in a binding site. To improve our understanding of the interaction between proteins and ligands in a binding site and the impact of networks, we need a clearer idea of protein flexibility.
We have developed a powerful tool that is able to measure flexibility at atomic positions. To do this we:
- established robust flexibility criteria based on retrospective analysis; to identify flexible regions in binding sites based on all available experimental structure data at each atomic position; and
- used these flexibility criteria in a predictive model – to forecast the flexibility of individual amino acids in apo or holo structures of binding sites, where little experimental data exists.;
Currently, the industry standard for determining protein flexibility is b factors. Neither b factors or other theoretical methods, currently in use across the field, are sufficiently sophisticated for our purposes. We needed to develop a method that determines flexibility at each atomic position and properly handles important factors such as symmetry issues and occupancy. In keeping with our company focus on genuine experimental data, rather than theoretical conjecture, we collated actual experimental data from both the public domain and private in-house crystal structure data to create a new method for identifying and measuring flexibility in proteins at atomic positions. This new, more accurate flexibility method is an important move forward for improved drug design.
The Residue Flexibility Tool (RFT) displays information based on high quality overlays of structures and the careful treatment of the differences in sequence identities and residue positions across sets of closely related proteins. By determining the differences we can identify small changes or movements caused by slightly different interactions. By building up this set of flexibility data, we can transpose the information into a usable software tool that calculates and predicts the movement. The result is a better understanding of the level of flexibility within the protein.
Specifically, this method/tool allows;
- improved ligand design and tighter binding – more flexible proteins will allow for a greater range of ligands to fit into the pockets;
- greater flexibility leads to enhanced selectivity; the more likely the drug is to hit its target, the lower the chances of off targets thereby reducing toxicity; and
- more ligands that can fit in a pocket increases the number of ligands to be patented and drugs to be made.
The Residue Flexibility Tool seamlessly links with Proasis3 and Profusion functionality, to provide you with unparalleled understanding of protein flexibility.