absence of the DNA [37–41] and identified loops L1 and L3 as the
most critical regions undergoing conformational changes (see
Notes 1 and 2). In other studies, the local consequences of phosphorylation have also been addressed, such as the phosphorylation
at S269 and S215, which also feature more distal effects, reducing
the affinity and specificity for DNA [42].
It is nowadays well established that despite the static view that
X-crystallography or the average ensembles of tens of conformation
that are deposited upon NMR structural determination, proteins
are highly dynamic entities that can undergo multiple conformational changes. Those changes can take place also on a broad range
of time scales [43–46]. They can account for small structural
changes in side-chain dihedrals and conformations or involve
more pronounced changes in loop conformations or even concerted motions of large regions or domains of a protein structure
[46]. The different states might be important for biological functions, and they can also be observed with different populations and
kinetics in both unbound/unmodified and bound/modified states
of a protein.
Of particular interest to understand the function of proteins so
complex as the super-hub p53 are those conformational changes
that are promoted long-range and that could unveil allosteric
mechanisms [46–49], i.e., those changes that occur at sites distal
from the modification or ligand-binding site. Allostery can manifest
in the form of both large conformational changes [50] but also
subtle localized changes in protein dynamics or structure [51].
In this view, it becomes crucial to understand how a biological
partner can exert its effect over long distances in p53, as well as
where the distal site interested by the distal communication is and
what is its function. Moreover, in the view of pre-existing minor
populated states of biological relevance, it is also important to
describe with accuracy if any of these conformational changes
induced long range are pre-existing in the free protein in solution
and how the population shift occurs.
An accurate understanding at the atom level could be achieved
by all-atom explicit solvent (see Note 1) MD simulations [52–54]
also coupled to NMR or other biophysical data that accounts for
the structural propensity over different time scales [45, 55–
57]. Indeed, all-atom MD, especially when coupled with enhanced
sampling techniques [58–60] provide information on protein
dynamics on timescales that go from the femto to the milliseconds.
In several applications of these methods, we are witnessing high
accuracy on the estimates of the different conformational states of
proteins and how mutations or post-translational modifications can
affect them [14, 61–65] and we finally have the tools to achieve a
detailed view of the free energy landscape associated with protein
conformational transitions (see Note 3).
Dynamics of p53
227
most critical regions undergoing conformational changes (see
Notes 1 and 2). In other studies, the local consequences of phosphorylation have also been addressed, such as the phosphorylation
at S269 and S215, which also feature more distal effects, reducing
the affinity and specificity for DNA [42].
It is nowadays well established that despite the static view that
X-crystallography or the average ensembles of tens of conformation
that are deposited upon NMR structural determination, proteins
are highly dynamic entities that can undergo multiple conformational changes. Those changes can take place also on a broad range
of time scales [43–46]. They can account for small structural
changes in side-chain dihedrals and conformations or involve
more pronounced changes in loop conformations or even concerted motions of large regions or domains of a protein structure
[46]. The different states might be important for biological functions, and they can also be observed with different populations and
kinetics in both unbound/unmodified and bound/modified states
of a protein.
Of particular interest to understand the function of proteins so
complex as the super-hub p53 are those conformational changes
that are promoted long-range and that could unveil allosteric
mechanisms [46–49], i.e., those changes that occur at sites distal
from the modification or ligand-binding site. Allostery can manifest
in the form of both large conformational changes [50] but also
subtle localized changes in protein dynamics or structure [51].
In this view, it becomes crucial to understand how a biological
partner can exert its effect over long distances in p53, as well as
where the distal site interested by the distal communication is and
what is its function. Moreover, in the view of pre-existing minor
populated states of biological relevance, it is also important to
describe with accuracy if any of these conformational changes
induced long range are pre-existing in the free protein in solution
and how the population shift occurs.
An accurate understanding at the atom level could be achieved
by all-atom explicit solvent (see Note 1) MD simulations [52–54]
also coupled to NMR or other biophysical data that accounts for
the structural propensity over different time scales [45, 55–
57]. Indeed, all-atom MD, especially when coupled with enhanced
sampling techniques [58–60] provide information on protein
dynamics on timescales that go from the femto to the milliseconds.
In several applications of these methods, we are witnessing high
accuracy on the estimates of the different conformational states of
proteins and how mutations or post-translational modifications can
affect them [14, 61–65] and we finally have the tools to achieve a
detailed view of the free energy landscape associated with protein
conformational transitions (see Note 3).
Dynamics of p53
227