  Allostery, the phenomenon by which the perturbation of a molecule at one site
alters its behavior at a remote functional site, enables control over
biomolecular function. Allosteric modulation is a promising avenue for drug
discovery and is employed in the design of mechanical metamaterials. However, a
general principle of allostery, i.e. a set of quantitative and transferable
"ground rules", remained elusive. It is neither a set of structural motifs nor
intrinsic motions. Focusing on elastic network models, we here show that an
allosteric lever--a mode-coupling pattern induced by the perturbation--governs
the directional, source-to-target, allosteric communication: a structural
perturbation of an allosteric site couples the excitation of localized hard
elastic modes with concerted long range soft-mode relaxation. Perturbations of
non-allosteric sites instead couple hard and soft modes uniformly. The
allosteric response is shown to be generally non-linear and non-reciprocal, and
allows for minimal structural distortions to be efficiently transmitted to
specific changes at distant sites. Allosteric levers exist in proteins and
"pseudoproteins"--networks designed to display an allosteric response.
Interestingly, protein sequences that constitute allosteric transmission
channels are shown to be evolutionarily conserved. To illustrate how the
results may be applied in drug design, we use them to successfully predict
known allosteric sites in proteins.
