2 research outputs found
Relation between Protein Intrinsic Normal Mode Weights and Pre-Existing Conformer Populations
Intrinsic
fluctuations of a protein enable it to sample a large
repertoire of conformers including the open and closed forms. These
distinct forms of the protein called conformational substates pre-exist
together in equilibrium as an ensemble independent from its ligands.
The role of ligand might be simply to alter the equilibrium toward
the most appropriate form for binding. Normal mode analysis is proved
to be useful in identifying the directions of conformational changes
between substates. In this study, we demonstrate that the ratios of
normalized weights of a few normal modes driving the protein between
its substates can give insights about the ratios of kinetic conversion
rates of the substates, although a direct relation between the eigenvalues
and kinetic conversion rates or populations of each substate could
not be observed. The correlation between the normalized mode weight
ratios and the kinetic rate ratios is around 83% on a set of 11 non-enzyme
proteins and around 59% on a set of 17 enzymes. The results are suggestive
that mode motions carry intrinsic relations with thermodynamics and
kinetics of the proteins
Arl2-Mediated Allosteric Release of Farnesylated KRas4B from Shuttling Factor PDEδ
Proper localization
of Ras proteins at the plasma membrane (PM)
is crucial for their functions. To get to the PM, KRas4B and some
other Ras family proteins bind to the PDEδ shuttling protein
through their farnesylated hypervariable regions (HVRs). The docking
of their farnesyl (and to a lesser extent geranylgeranyl) in the hydrophobic
pocket of PDEδ’s stabilizes the interaction. At the PM,
guanosine 5′-triphosphate (GTP)-bound Arf-like protein 2 (Arl2)
assists in the release of Ras from the PDEδ. However, exactly
how is still unclear. Using all-atom molecular dynamics simulations,
we unraveled the detailed mechanism of Arl2-mediated release of KRas4B,
the most abundant oncogenic Ras isoform, from PDEδ. We simulated
ternary Arl2–PDEδ−KRas4B HVR complexes and observed
that Arl2 binding weakens the PDEδ−farnesylated HVR interaction.
Our detailed analysis showed that allosteric changes (involving β6
of PDEδ and additional PDEδ residues) compress the hydrophobic
PDEδ pocket and push the HVR out. Mutating PDEδ residues
that mediate allosteric changes in PDEδ terminates the release
process. Mutant Ras proteins are enriched in human cancers, with currently
no drugs in the clinics. This mechanistic account may inspire efforts
to develop drugs suppressing oncogenic KRas4B release