therefore, a poorer catalyst than proteins. As a result, only a handful
of protein-free RNA-based enzymes have evolved [3], which most
often cleave the RNA backbone without the regulatory input of
other molecules. Interestingly, these enzymes, called ribozymes, do
not typically display allosteric changes as a result of binding an
effector molecule outside of the active site; rather, they are able to
act independently of interacting partners or ligands. However,
conformational transitions accompany the assembly of practically
all RNA-ligand complexes, and since they involve ligand-induced
changes, they can be broadly defined as allosteric changes. In
contrast to proteins, RNA folding involves many structural adaptations upon binding to Mg
2+ cations, which are essential for neutralizing the negative charge of phosphate moieties in the RNA
backbone and which make possible formation of secondary and
tertiary RNA structures. Each of these cation-mediated folding
transitions could also be considered as allosteric modulations of
the RNA structure.
Many researchers focus their efforts on studying the interplay
between RNA structure transitions and ligand binding, providing
an enormous number of examples of allosteric modulations in RNA
(reviewed in [4, 5]). However, one aspect closely related to allostery remains poorly understood due to methodological difficulties
and the complexity of studied systems. This aspect pertains to
coordination of molecular events in order to overcome the time
constraints imposed by sampling the vast number of various conformations and quickly narrowing down the options to the final
functional state. Such a coordination can involve interdependence
of molecular events, a phenomenon observed in many biological
systems and defined by the thermodynamic term “cooperativity”
[5]. In RNA systems, cooperative binding is often based on allosteric changes introduced by initial ligand binding and is therefore of
high importance for understanding the functions of many
RNA-containing assemblies.
Cooperativity and allostery have long been known to researchers as the most basic biological principles. Cooperativity was first
described as the change in ligand-binding affinity observed upon
the binding of another, identical ligand (reviewed in [6]). One of
the earliest examples of this phenomenon was the tetrameric hemoglobin molecules [7] composed of four identical monomers each
capable of binding to a single oxygen molecule. Upon the binding
of the first oxygen molecule, the protein undergoes an allosteric
change that increases the binding affinity for oxygen in the other
monomers, allowing each subsequent oxygen molecule to bind
more easily, represented by a sigmoidal binding curve. Over the
years, the meaning of the term cooperativity has broadened from
the classical description of ligands binding to multiple sites of an
oligomeric protein, as in hemoglobin, to interdependent
256
Alla Peselis and Alexander Serganov
of protein-free RNA-based enzymes have evolved [3], which most
often cleave the RNA backbone without the regulatory input of
other molecules. Interestingly, these enzymes, called ribozymes, do
not typically display allosteric changes as a result of binding an
effector molecule outside of the active site; rather, they are able to
act independently of interacting partners or ligands. However,
conformational transitions accompany the assembly of practically
all RNA-ligand complexes, and since they involve ligand-induced
changes, they can be broadly defined as allosteric changes. In
contrast to proteins, RNA folding involves many structural adaptations upon binding to Mg
2+ cations, which are essential for neutralizing the negative charge of phosphate moieties in the RNA
backbone and which make possible formation of secondary and
tertiary RNA structures. Each of these cation-mediated folding
transitions could also be considered as allosteric modulations of
the RNA structure.
Many researchers focus their efforts on studying the interplay
between RNA structure transitions and ligand binding, providing
an enormous number of examples of allosteric modulations in RNA
(reviewed in [4, 5]). However, one aspect closely related to allostery remains poorly understood due to methodological difficulties
and the complexity of studied systems. This aspect pertains to
coordination of molecular events in order to overcome the time
constraints imposed by sampling the vast number of various conformations and quickly narrowing down the options to the final
functional state. Such a coordination can involve interdependence
of molecular events, a phenomenon observed in many biological
systems and defined by the thermodynamic term “cooperativity”
[5]. In RNA systems, cooperative binding is often based on allosteric changes introduced by initial ligand binding and is therefore of
high importance for understanding the functions of many
RNA-containing assemblies.
Cooperativity and allostery have long been known to researchers as the most basic biological principles. Cooperativity was first
described as the change in ligand-binding affinity observed upon
the binding of another, identical ligand (reviewed in [6]). One of
the earliest examples of this phenomenon was the tetrameric hemoglobin molecules [7] composed of four identical monomers each
capable of binding to a single oxygen molecule. Upon the binding
of the first oxygen molecule, the protein undergoes an allosteric
change that increases the binding affinity for oxygen in the other
monomers, allowing each subsequent oxygen molecule to bind
more easily, represented by a sigmoidal binding curve. Over the
years, the meaning of the term cooperativity has broadened from
the classical description of ligands binding to multiple sites of an
oligomeric protein, as in hemoglobin, to interdependent
256
Alla Peselis and Alexander Serganov