320

23

Regulatory Networks

In contrast, properly designed in vitro experiments can reconstitute conditions of a

tightly defined, spatially restricted physiological state of a living cell.

It should be emphasized that many protein interactions take place at the internal

surfaces of cells, such as the various lipid bilayer membranes. The physical chemistry

of the interactome is thus largely the physical chemistry of heterogeneous reactions,

not homogeneous ones. It also follows that the interactions of the proteins with

these internal surfaces must also be investigated: Clearly, a situation in which two

potentially interacting partners become associated with a membrane, and then diffuse

laterally until they encounter each other, is different from one in which only one

protein is associated with the membrane, and the interacting partner remains in the

bulk.

The field can naturally be extended to include the interactions of proteins with

other nonprotein objects, such as DNA, RNA, oligosaccharides, and polysaccharides,

as well as lipid membranes. Indeed, it is essential to do so in order to obtain a proper

representation of the working of a cell. Although the interactome emerged from

a consideration of proteins, protein–DNA and protein–saccharide interactions are

exceedingly important in the cell (the latter have been given comparatively less

attention). ²³

One proposed simplification has been to consider that protein–protein binding

takes place via a relatively small number of characteristic polypeptide domains (i.e.,

a sequence of contiguous amino acids, sometimes referred to as a “module”). In the

language of immunology, a binding module is an epitope (cf. Sect. 14.6). The module

concept implies that the interactome could effectively be considerably reduced in

size. There is, however, no consistent way of defining the modules. It seems clear

that a sequence of contiguous amino acids is inadequate to do so; an approach built

upon the dehydron concept ²⁴ would appear to be required.

It is useful to consider two types of protein complexes: “permanent” and “tran-

sient”. By permanent, large multiprotein complexes such as the spliceosome (and,

in principle, any multisubunit protein) that remain intact during the lifetime of their

constituents are meant. On the other hand, transient complexes form and disintegrate

constantly as and when required. The interactome is thus a highly dynamic structure

and this kinetic aspect needs to be included in any complete characterization.

The kinetic mass action law (KMAL) defines the same upper KK as given in Eq. (23.7)

according to

upper K equals StartFraction k Subscript normal a Baseline Over k Subscript normal d Baseline EndFraction commaK = ^ka

kd

,

(23.8)

where the kks are the rate coefficients for association (a) and dissociation (d), but as

it is a ratio, the same value of upper KK results from association reactions that take either

milliseconds or years to reach equilibrium. This temporal aspect can have profound

influences on the outcome of a complex interaction. Many biological transformations

23 Remarkable specificity is achievable (see, e.g., Popescu and Misevic 1997).

24 The dehydron (Sect. 15.5.2) is an underwrapped (i.e., underdesolvated) hydrogen bond and is a

key determinant of protein affinity. See also Fernández (2015).