89
Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session I
36-POS
Board 36
Modulating of Protein Stability by Modifications
Yulian Gavrilov
.
Weizmann Institute of Science, Rehovot, Israel.
A quite conventional way to change the thermodynamic stability of a protein is to control the
unfolded state entropy and the folded state enthalpy. In principle, it should also be possible to
regulate the enthalpy of the unfolded state and the entropy of the folded state. Here, we present
several studies to illustrate that various protein modifications (PM) can change the
thermodynamic stability of a protein in different ways. Using computational and experimental
techniques we showed that shortening the L4 loop of the hmACP protein by six residues results
in a strong stabilization. Surprisingly this effect was due to increasing the entropy of the folded
state. Furthermore, we demonstrated that this mechanism is not exclusive for this system. In fact
also the ubiquitination on the Ubc7 protein results in entropic destabilization. This is mostly due
to reduction of the conformational flexibility of the loop region. In both studies the effect on the
protein loop regions was critical. Glycosylation usually results in the stabilization of the protein
but experimentally it was shown that the MM1 protein was destabilized by attaching of N-
acetylgalactosamine. Using computational tools we found that attached sugars strongly interact
with the protein, which leads to the disruption of the intramolecular native contacts. Most likely,
the observed destabilization is related to these conformational changes.
Experiments have revealed that the effect of modifications of the PinWW protein depends on the
type (Glycosylation/PEGylation) and site of the modification. Our computational study shed
light on the molecular origin of experimentally reported effect of each modification of the
stability of the PinWW. These examples illustrate the complex effect of modifications on the
thermodynamic stability of proteins and may provide some principle for manipulating protein
properties.
