Shortening a loop can increase protein native state entropy

Abstract

Protein loops are essential structural elements that influence not only function but also protein stability and folding rates. It was recently reported that shortening a loop in the AcP protein may increase its native state conformational entropy. This effect on the entropy of the folded state can be much larger than the lower entropic penalty of ordering a shorter loop upon folding, and can therefore result in a more pronounced stabilization than predicted by polymer model for loop closure entropy. In this study, which aims at generalizing the effect of loop length shortening on native state dynamics, we use all-atom molecular dynamics simulations to study how gradual shortening a very long or solvent-exposed loop region in four different proteins can affect their stability. For two proteins, AcP and Ubc7, we show an increase in native state entropy in addition to the known effect of the loop length on the unfolded state entropy. However, for two permutants of SH3 domain, shortening a loop results only with the expected change in the entropy of the unfolded state, which nicely reproduces the observed experimental stabilization. Here, we show that an increase in the native state entropy following loop shortening is not unique to the AcP protein, yet nor is it a general rule that applies to all proteins following the truncation of any loop. This modification of the loop length on the folded state and on the unfolded state may result with a greater effect on protein stability.

Identification of the critical residues responsible for differential reactivation of the triosephosphate isomerases of two trypanosomes

“…In the cases of region 2, residues at positions 43 and 46 (which affect monomer association) are in interfacial loop 2 and amino acids at positions 56 and 57 are in external loop 2. Several studies have shown that loops play an important role in protein folding, because the contacts that they form with the rest of the polypeptide chain limit the available conformational space, accelerating or slowing down the process [27][28][29][30]. Thus, the position of these amino acids in the loops could be a factor that guides the folding in these proteins and the difference in their reactivation could be due to the interactions formed in the initial points of folding or to the dihedral angles formed by the side chains of these amino acids.…”

Backbone Circularization Coupled with Optimization of Connecting Segment in Effectively Improving the Stability of Granulocyte-Colony Stimulating Factor

“…Polypeptides (proteins and oligopeptides) are the fundamental building block of organisms but generally suffer from the problem of low stability when administered to the body as therapeutics. The addition of some covalent bonds is the most basic strategy of stabilization for a large number of natural proteins and has been successfully applied in protein engineering. , On the other hand, loop truncation is also broadly accepted as effective in enhancing protein stability, although the increase in the stability and the effect on the function are difficult to predict. − We expect that superstable protein can be obtained by a method that combined these strategies, i.e., circularization with appropriate truncation of the terminal connecting segment.…”

Biochemical Characterization and Mutational Analysis of a Lactone Hydrolase from Phialophora americana

“…Loops are an integral structural component that affect the protein flexibility/rigidity pattern and catalytic efficiency. , Region 133–164 in the cap domain of RmZHD and ZHD101 structure is the most variable part according to sequence alignment. Furthermore, the β6−α5 loop of RmZHD is closer to the substrate-binding pocket, leading to high catalytic efficiency against ZEN and α-ZOL compared to ZHD101 .…”