Statistical mechanics of the histone code

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.