For allosteric communication to be effective and transmit DOF
and change in shape across long-range distances across protein
networks, the delicate balance between rigidity and flexibility is
critical. Some large rigid components (i.e., helices which are great
at transmissions over large distances) and connecting flexible
regions are needed to observe long-distance propagation. We can
see this by observing the range of energy cutoffs where transmission
occurs and the corresponding rigid cluster decomposition. We see
no allosteric transmission when the protein is either overly rigid or
overly flexible (see Fig. 2a, d).
The two agonists adenosine and NECA are structurally very
similar, and interestingly produce a very similar DOF transmission
allostery profiles. Previous studies have shown that the two configurations of adenosine- and NECA-bound crystal structures are in a
partially active state [31]. On the other hand, the authors in [32]
report that the UKA-bound agonist crystal structure is in active
state conformation (fully active state is reached in presence of
G-protein). Moreover, UKA is a stronger agonist of the three
agonists considered here. This may point to why adenosine- and
NECA-bound structures transmit DOF at an almost identical
hydrogen bond energy range, whereas UKA-bound receptor is
more effective in allosteric transmission as it transmits more DOF
and also at an earlier and wider range of energy cutoffs.
3 Notes and Conclusions
The progress over the last 20 years in the field of mathematical
rigidity theory has opened up a number of exciting avenues for
analyzing the close relationship between protein function, flexibility, and dynamics. A straightforward method that describes how
allosteric signals are transmitted across protein structures and
describes a mechanistic insight into allosteric propagation has
been previously difficult to design and conceptualize. Our novel
model of allosteric communication via transmission of degrees of
freedom across protein networks and RTA analysis offers a new
window to study the allosteric cross-talk between remotes sites in
proteins. In this initial methodology expose, we have shown how
RTA analysis can be a powerful tool for probing allostery which also
provides a strong case for a mechanistic interpretation of mysterious
allosteric transmission and regulation. RTA analysis was recently
applied on a bacterial homodimeric enzyme fluoracetate dehalogenase where we predicted and accurately demonstrated the presence of physical allosteric pathways between the two protomers as a
key functional control of the enzyme catalysis, which is closely
supported and validated by experimental data [10] with other
applications in detection of allosteric sites in GPCRs and in epitope
mapping. Forthcoming work (to appear) will reveal further novel
Probing Allosteric Mechanism with Rigidity Transmission
73
and change in shape across long-range distances across protein
networks, the delicate balance between rigidity and flexibility is
critical. Some large rigid components (i.e., helices which are great
at transmissions over large distances) and connecting flexible
regions are needed to observe long-distance propagation. We can
see this by observing the range of energy cutoffs where transmission
occurs and the corresponding rigid cluster decomposition. We see
no allosteric transmission when the protein is either overly rigid or
overly flexible (see Fig. 2a, d).
The two agonists adenosine and NECA are structurally very
similar, and interestingly produce a very similar DOF transmission
allostery profiles. Previous studies have shown that the two configurations of adenosine- and NECA-bound crystal structures are in a
partially active state [31]. On the other hand, the authors in [32]
report that the UKA-bound agonist crystal structure is in active
state conformation (fully active state is reached in presence of
G-protein). Moreover, UKA is a stronger agonist of the three
agonists considered here. This may point to why adenosine- and
NECA-bound structures transmit DOF at an almost identical
hydrogen bond energy range, whereas UKA-bound receptor is
more effective in allosteric transmission as it transmits more DOF
and also at an earlier and wider range of energy cutoffs.
3 Notes and Conclusions
The progress over the last 20 years in the field of mathematical
rigidity theory has opened up a number of exciting avenues for
analyzing the close relationship between protein function, flexibility, and dynamics. A straightforward method that describes how
allosteric signals are transmitted across protein structures and
describes a mechanistic insight into allosteric propagation has
been previously difficult to design and conceptualize. Our novel
model of allosteric communication via transmission of degrees of
freedom across protein networks and RTA analysis offers a new
window to study the allosteric cross-talk between remotes sites in
proteins. In this initial methodology expose, we have shown how
RTA analysis can be a powerful tool for probing allostery which also
provides a strong case for a mechanistic interpretation of mysterious
allosteric transmission and regulation. RTA analysis was recently
applied on a bacterial homodimeric enzyme fluoracetate dehalogenase where we predicted and accurately demonstrated the presence of physical allosteric pathways between the two protomers as a
key functional control of the enzyme catalysis, which is closely
supported and validated by experimental data [10] with other
applications in detection of allosteric sites in GPCRs and in epitope
mapping. Forthcoming work (to appear) will reveal further novel
Probing Allosteric Mechanism with Rigidity Transmission
73