113
Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session II
58-POS
Board 11
Allosteric Communication within the B-Raf Dimer: The Effect of the V600E Mutation and
Inhibitor Binding
Kristen Marino
, Francesco L. Gervasio.
University College London, London, United Kingdom.
Kinase proteins play a fundamental role in cellular signaling: by transferring a phosphate group
from ATP to specific target molecules they are able to modify their activity and consequently
regulate cell function. Given the importance of kinases in regulating most of the cellular
responses, it is not surprising that aberrant activation of kinases is one of the major causes of
human diseases, including cancer, making them fundamental targets for drug design.
Conformational transitions play a central role in kinase regulation. X-ray structures have shown
that kinases adopt an active state that is maximally active and one or more inactive states that
show minimal activity.
The V600E mutation of B-Raf is one of the most common in metastatic melanomas. This
mutation is expected to shift the balance between the active and inactive forms of the kinase
towards the former. Thus B-Raf appears to be a promising target in the treatment of melanoma.
Complicating drug design efforts, some ATP-competitive B-Raf inhibitors induce a “paradoxical
activation” of the Raf pathway. From experimental evidence it has been deduced that drug
binding promotes dimerization, and that when a drug-bound monomer dimerizes with an apo-
monomer, the apo-monomer adopts an active conformation. Unfortunately, a clear picture of B-
Raf dimerization and allosteric communication within the dimer are lacking. Using all-atom
molecular dynamics simulations and the metadynamics enhanced sampling method, we can
identify the effect of the V600E mutation and drug binding on the allosteric networks within the
dimer, which is difficult to obtain experimentally. This knowledge could greatly contribute to the
development of more effective and selective drugs and to counter the emergence of resistance to
drugs currently in clinical use.
