Cooperative protein allosteric transition mediated by a fluctuating transmission network

Abstract

Allosteric communication between distant protein sites represents a key mechanism of biomolecular regulation and signal transduction. Compared to other processes such as protein folding, however, the dynamical evolution of allosteric transitions is still not well understood. As example of allosteric coupling between distant protein regions, we consider the global open-closed motion of the two domains of T4 lysozyme, which is triggered by local motions in the hinge region. Combining extensive molecular dynamics simulations with machine learning of contact features, we identify a network of interresidue distances that move in a concerted manner. The cooperative process originates from a cogwheel-like motion of the hydrophobic core in the hinge region, which constitutes a flexible transmission network. Through rigid contacts and the protein backbone, the small local changes of the hydrophobic core are passed on to the distant terminal domains and lead to the emergence of a rare global conformational transition. As in an Ising-type model, the cooperativity of the allosteric transition can be explained via the interaction of local fluctuations.

Nonequilibrium Modeling of the Elementary Step in PDZ3 Allosteric Communication

“…On the other hand, we expect that the main finding, i.e., that allosteric communication is mediated through a concerted conformational transition that involves numerous simultaneous contact changes, prevails also in the absence of direct contacts and therefore represents a general result. For example, Post et al 44 found a quite similar scenario for the allosteric coupling in T4 lysozyme.…”

“…To identify internal coordinates that change significantly during the conformational transition, we follow recent work 43,44 and focus on interresidue contact distances. This is for two reasons.…”

“…First, although contact distances report only on near-order interactions, long-distance changes of the structure result as a consequence and are therefore included as well. Moreover, while side-chain dihedral angles may also mediate allosteric couplings, 44,45 analyses including them showed that they are not of relevance for PDZ3. Assuming that a contact is formed if the distance r ij between the closest non-hydrogen atoms of residues i and j is shorter than 4.5 Å, 46 we identified 403 interresidue contacts (see SI Methods).…”

“…That is, all contacts change almost simultaneously, similar to the cooperative mechanism that was observed in the functional dynamics of T4 lysozyme. 44 Starting in the relatively ordered cis state, the system becomes disordered upon cis-to-trans photoswitching and returns to an ordered state via a cooperative transition. In this way, the system follows a order-disorder-order transition, which was also observed for a photoswitchable PDZ2 domain.…”

Correlation-based feature selection to identify functional dynamics in proteins

“…3c, which shows that these distances span the space connecting the mouth and hinge regions, and therefore reflect the allosteric coupling between these two distant regions. 69 Largely uncorrelated to cluster 1, clusters 2 and 3 account for other correlated motions of T4L. As shown in Fig.…”