Modulation of hemoglobin dynamics by an allosteric effector

Abstract

Hemoglobin (Hb) is an extensively studied paradigm of proteins that alter their function in response to allosteric effectors. Models of its action have been used as prototypes for structure‐function relationships in many proteins, and models for the molecular basis of its function have been deeply studied and extensively argued. Recent reports suggest that dynamics may play an important role in its function. Relatively little is known about the slow, correlated motions of hemoglobin subunits in various structural states because experimental and computational strategies for their characterization are challenging. Allosteric effectors such as inositol hexaphosphate (IHP) bind to both deoxy‐Hb and HbCO, albeit at different sites, leading to a lowered oxygen affinity. The manner in which these effectors impact oxygen binding is unclear and may involve changes in structure, dynamics or both. Here we use neutron spin echo measurements accompanied by wide‐angle X‐ray scattering to show that binding of IHP to HbCO results in an increase in the rate of coordinated motions of Hb subunits relative to one another with little if any change in large scale structure. This increase of large‐scale dynamics seems to be coupled with a decrease in the average magnitude of higher frequency modes of individual residues. These observations indicate that enhanced dynamic motions contribute to the functional changes induced by IHP and suggest that they may be responsible for the lowered oxygen affinity triggered by these effectors.

Dynamics of proteins in solution

“…Lal et al . (2017) and Matsuo et al . (2017) below, and section ‘Collective internal motions in proteins’), it seems however not easy to disentangle the effect of quaternary structure changes from a possible allosteric effect 1 .…”

“…Lal et al . (2017) employed NSE at scattering vectors 0.1 Å −1 < q <1 Å −1 to study allosteric effects in Hb. They observed a change in the dynamics of Hb upon ligandation of the allosteric effector inositol hexaphosphate (IHP), which leads to a lowered oxygen affinity in both deoxy-Hb and HbCO.…”

“…In light of recent studies showing how the protein internal dynamics can be modulated by the bonding of a ligand also without major structural changes (see e.g. Lal et al (2017) and Matsuo et al (2017) below, and section 'Collective internal motions in proteins'), it seems however not easy to disentangle the effect of quaternary structure changes from a possible allosteric effect 1 . Lal et al (2017) employed NSE at scattering vectors 0.1 Å −1 <q <1 Å −1 to study allosteric effects in Hb.…”

“…Lal et al (2017) and Matsuo et al (2017) below, and section 'Collective internal motions in proteins'), it seems however not easy to disentangle the effect of quaternary structure changes from a possible allosteric effect 1 . Lal et al (2017) employed NSE at scattering vectors 0.1 Å −1 <q <1 Å −1 to study allosteric effects in Hb. They observed a change in the dynamics of Hb upon ligandation of the allosteric effector inositol hexaphosphate (IHP), which leads to a lowered oxygen affinity in both deoxy-Hb and HbCO.…”

Conceptual DFT study of the chemical reactivity of four natural products with anti-sickling activity

“…10). According to Lal et al [63], inositol hexaphosphate (IHP) binds to deoxyhemoglobin and leads to a lowered oxygen affinity, but the manner in which this effector impacts oxygen binding is unclear and may involve changes in structure, dynamics. The docking calculations predict the binding energy between IHP and 2HHB of − 25.01 kcal/mol and characterized by seven P=O…H hydrogen bonds ranging between 1.715 − 2.463 Å involving Val-1, Hsd-2, and Lys-82 residues.…”