Collective Dynamics Underlying Allosteric Transitions in Hemoglobin

Martin D Vesper,Bert L De Groot,Dennis R Livesay

doi:10.1371/journal.pcbi.1003232

Martin D Vesper, Bert L De Groot + Show 1 more

Open Access

https://doi.org/10.1371/journal.pcbi.1003232

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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.

Highlights

Hemoglobin (Hb) consists of two a and two b protein chains that bind oxygen to a heme group for the transport through the blood
Molecular Dynamics Simulations From the Hb simulations carried out by Hub and co-workers
It is known that the four protein chains of hemoglobin – each containing one oxygen binding site – need to rearrange globally or the cooperativity is lost

Summary

Introduction

Hemoglobin (Hb) consists of two a and two b protein chains that bind oxygen to a heme group for the transport through the blood. These binding sites act cooperatively, i.e. the binding affinity for O2 in one site is increased after O2 binding in one of the other sites. Many high-resolution structures are available, including oxy states, deoxy states, carbon monoxide bound structures and structures of a large number of point mutations [10]. Dynamical information is obtained from e.g. spectroscopic studies, observing transition states in the oxy to deoxy transition, and analysing specific bonds during CO dissociation [11]

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