  The intricate pattern of chemical modifications on DNA and histones, the
"histone code", is considered to be a key gene regulation factor. Multivalency
is seen by many as an essential instrument to transmit the "encoded"
information to the transcription machinery via multi-domain effector proteins
and chromatin-associated complexes. However, as examples of multivalent histone
engagement accumulate, an apparent contradiction is emerging. The isolated
effector domains are notably weak binders, thus it is often asserted that the
entropic cost of orienting multiple domains can be "prepaid" by a rigid tether.
Meanwhile, evidence suggests that the tethers are largely disordered and offer
little rigidity. Here we consider a mechanism to "prepay" the entropic costs of
orienting the domains for binding, not through rigidity of the tether but
through the careful spacing of the modifications on chromatin. An all-atom
molecular dynamics study of the most fully characterized multivalent chromatin
effector conforms to the conditions for an optimal free-energy payout, as
predicted by the model discussed here.
