The intricate pattern of chemical modifications on the 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 mediate the transmission of the "encoded" information to the transcription machinery via multi- domain effector proteins and chromatin-associated complexes. However, the physical model explaining the critical role of multivalency for the histone code is still lacking. Here, we propose a theory that explains the energetic " payout " of multivalency in the formalism of statistical mechanics. The model quantifies the dependence of binding entropy in a multivalent system on the geometry and flexibility of the binding partners . An all-atom molecular dynamics study of a relevant biological system involving the multivalent chromatin effector UHRF1 and its target histone H3 demonstrate that this interaction conforms to the conditions for an optimal free-energy payout, as predicted by the model  .
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 .
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the physical model explaining the critical role of multivalency for the histone code is still lacking. Here, we propose a theory that explains the energetic
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
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payout
prepaid
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of multivalency in the formalism of statistical mechanics. The model quantifies the dependence of binding entropy in a multivalent system on the geometry and flexibility of the binding partners
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
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UHRF1 and its target histone H3 demonstrate that this interaction
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