Collective Dynamics Underlying Allosteric Transitions in Hemoglobin

Abstract

Hemoglobin is the prototypic allosteric protein. Still, its molecular allosteric mechanism is not fully understood. To elucidate the mechanism of cooperativity on an atomistic level, we developed a novel computational technique to analyse the coupling of tertiary and quaternary motions. From Molecular Dynamics simulations showing spontaneous quaternary transitions, we separated the transition trajectories into two orthogonal sets of motions: one consisting of intra-chain motions only (referred to as tertiary-only) and one consisting of global inter-chain motions only (referred to as quaternary-only). The two underlying subspaces are orthogonal by construction and their direct sum is the space of full motions. Using Functional Mode Analysis, we were able to identify a collective coordinate within the tertiary-only subspace that is correlated to the most dominant motion within the quaternary-only motions, hence providing direct insight into the allosteric coupling mechanism between tertiary and quaternary conformation changes. This coupling-motion is substantially different from tertiary structure changes between the crystallographic structures of the T- and R-state. We found that hemoglobin's allosteric mechanism of communication between subunits is equally based on hydrogen bonds and steric interactions. In addition, we were able to affect the T-to-R transition rates by choosing different histidine protonation states, thereby providing a possible atomistic explanation for the Bohr effect.

The Dynamic Behavior of the P2X4 Ion Channel in the Closed Conformation

“…In this case, the rigid-body motions describe the interchain movements whereas the internal motions describe the intrachain movements (i.e., deformations of each chain). Recently, Vesper and de Groot presented a simple procedure to separate these two contributions (37). We implemented their method to study the fluctuations of the closed form of the P2X 4 receptor, as well as to analyze the closed/open transition.…”

Identifying coupled clusters of allostery participants through chemical shift perturbations

“…Many experimental studies have focused on elucidating the molecular mechanism by which the perturbation is propagated within or between the functional units (5,6), for example, by identifying changes in close contacts between specific residues that are responsible for allostery. Computational methods, such as molecular dynamics simulations, have complemented these experimental strategies by identifying correlated motions of residues, which further clarify the atomistic mechanism by which these residues participate in allostery (6)(7)(8). It has been emphasized that there may not be a single set of conformational changes underlying the allostery; rather, ligand binding may shift the protein's conformational and dynamic ensemble, resulting in changes in thermodynamics and affinity at distant sites (9-11).…”

Induced Fit in Protein Multimerization: The HFBI Case

“…This rotation leads to a variation of the electrostatic potential at the C/D interface (Fig 5) and to the formation of contacts that reduce the possibility of β -hairpin opening (Fig 7 and S3 Table). This coupling between quaternary and tertiary structure rearrangements has been well studied, for example, in hemoglobin [40, 41]. On the other hand, looking at the tetramer( coc c ), where one chain is already in conformation o , an intermediate behaviour between the monomer and the dimer can be observed in term of FES (Figs 2D and 3).…”