Abstract
Although the critical role of allostery in controlling enzymatic processes is well appreciated, there is a current dearth in our understanding of its underlying mechanisms, including communication between binding sites. One potential key aspect of intersite communication is the mechanical coupling between residues in a protein. Here, we introduce a graph-based computational approach to investigate the mechanical coupling between distant parts of a protein, highlighting effective pathways via which protein motion can transfer energy between sites. In this method, each residue is treated as a node on a weighted, undirected graph, in which the edges are defined by locally correlated motions of those residues and weighted by the strength of the correlation. The method was validated against experimental data on allosteric regulation in the human liver pyruvate kinase as obtained from full-protein alanine-scanning mutagenesis (systematic mutation) studies, as well as computational data on two G-protein-coupled receptors. The method provides semiquantitative information on the regulatory importance of specific structural elements. It is shown that these elements are key for the mechanical coupling between distant parts of the protein by providing effective pathways for energy transfer. It is also shown that, although there are a multitude of energy transfer pathways between distant parts of a protein, these pathways share a few common nodes that represent effective “chokepoints” for the communication.
| Original language | English |
|---|---|
| Journal | Biophysical Journal |
| DOIs | |
| Publication status | Published - Jan 1 2019 |
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ASJC Scopus subject areas
- Biophysics
Cite this
Chokepoints in Mechanical Coupling Associated with Allosteric Proteins : The Pyruvate Kinase Example. / Johnson, Lewis E.; Ginovska, Bojana; Fenton, Aron W.; Raugei, Simone.
In: Biophysical Journal, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Chokepoints in Mechanical Coupling Associated with Allosteric Proteins
T2 - The Pyruvate Kinase Example
AU - Johnson, Lewis E.
AU - Ginovska, Bojana
AU - Fenton, Aron W.
AU - Raugei, Simone
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Although the critical role of allostery in controlling enzymatic processes is well appreciated, there is a current dearth in our understanding of its underlying mechanisms, including communication between binding sites. One potential key aspect of intersite communication is the mechanical coupling between residues in a protein. Here, we introduce a graph-based computational approach to investigate the mechanical coupling between distant parts of a protein, highlighting effective pathways via which protein motion can transfer energy between sites. In this method, each residue is treated as a node on a weighted, undirected graph, in which the edges are defined by locally correlated motions of those residues and weighted by the strength of the correlation. The method was validated against experimental data on allosteric regulation in the human liver pyruvate kinase as obtained from full-protein alanine-scanning mutagenesis (systematic mutation) studies, as well as computational data on two G-protein-coupled receptors. The method provides semiquantitative information on the regulatory importance of specific structural elements. It is shown that these elements are key for the mechanical coupling between distant parts of the protein by providing effective pathways for energy transfer. It is also shown that, although there are a multitude of energy transfer pathways between distant parts of a protein, these pathways share a few common nodes that represent effective “chokepoints” for the communication.
AB - Although the critical role of allostery in controlling enzymatic processes is well appreciated, there is a current dearth in our understanding of its underlying mechanisms, including communication between binding sites. One potential key aspect of intersite communication is the mechanical coupling between residues in a protein. Here, we introduce a graph-based computational approach to investigate the mechanical coupling between distant parts of a protein, highlighting effective pathways via which protein motion can transfer energy between sites. In this method, each residue is treated as a node on a weighted, undirected graph, in which the edges are defined by locally correlated motions of those residues and weighted by the strength of the correlation. The method was validated against experimental data on allosteric regulation in the human liver pyruvate kinase as obtained from full-protein alanine-scanning mutagenesis (systematic mutation) studies, as well as computational data on two G-protein-coupled receptors. The method provides semiquantitative information on the regulatory importance of specific structural elements. It is shown that these elements are key for the mechanical coupling between distant parts of the protein by providing effective pathways for energy transfer. It is also shown that, although there are a multitude of energy transfer pathways between distant parts of a protein, these pathways share a few common nodes that represent effective “chokepoints” for the communication.
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UR - http://www.scopus.com/inward/citedby.url?scp=85064428976&partnerID=8YFLogxK
U2 - 10.1016/j.bpj.2019.03.026
DO - 10.1016/j.bpj.2019.03.026
M3 - Article
C2 - 31010662
AN - SCOPUS:85064428976
JO - Biophysical Journal
JF - Biophysical Journal
SN - 0006-3495
ER -