Protein flexibility. Role in allostery and variability in thermophilic and mesophilic organisms

Main Research line: Protein dynamics and enzyme catalysis
Main Researcher: Ramon Crehuet

Proteins are flexible dynamical entities. The role of dynamics has challenged the sequence-structure-function paradigm of structural biology by introducing a fourth term: sequence-structure-dynamics-function.

Protein dynamics spans a vast time-scale and amplitude scale: from local jiggling of residues to protein domain motions. Diferent computational (and experimental!) tools are needed to sample conformations at these different time scales.

What we do
Evolution can tinker with protein dynamics in different ways. We have studied two them. First, dynamics adapt proteins to different temperatures. Second, oligomerization affects the dynamics of the building monomers.

Protein dynamics in solution can be studied with neutron scattering spectroscopy. The results found by Zaccai and co-workers suggested that thermophilic enzymes were not sensitive to temperature changes, even though they were more flexible than their mesophilic homologues. This was a surprising result as an increased rigidity is considered one of the adaptations to high temperature.

Our research revealed that diffusion need to be also taken into account, and the diffusive behaviour of the proteins in the experimental crowded medius differed for the thermophilic and mesophilic proteins. Our multi-scale simulations of the neutron scattering results gave an alternative explanation to the same experimental data that was more in agreement with previous knowledge of protein stability.[1, 2]

A second research field explores the how the monomer contacts in a multimeric protein affect their dynamics. For this we used the N-acetylglutamate kinase family which contains monomeric and dimeric and hexameric proteins. We showed that even though the dynamics within a family is conserved, the shape and type of interface between the monomers modulates how dynamics is transferred between the subunits. This allows subunits to communicate with each other, giving rise to allosterism. [3, 4] This research was done in collaboration with Ivet Bahar.

Software
In this line of research, we use Gromacs and coarse-grained protein models to calculate normal modes, such as ProDy.

As IDPs are so flexible, their properties can only be calculated from large ensembles of structures.

As IDPs are so flexible, their properties can only be calculated from large ensembles of structures.

Related publications

Marcos, E.; Jiménez, A.; Crehuet, R, Dynamic Fingerprints of Protein Thermostability Revealed by Long Molecular Dynamics, J. Chem. Theory Comput, 2012, 8 (3), 1129–1142

Marcos, E.; Mestres, P.; Crehuet, R, Crowding Induces Differences in the Diffusion of Thermophilic and Mesophilic Proteins: A New Look at Neutron Scattering Results, Biophys. J, 2011, 101 (11), 2782–2789

Marcos, E.; Crehuet, R.; Bahar, I, Changes in Dynamics upon Oligomerization Regulate Substrate Binding and Allostery in Amino Acid Kinase Family Members., PLoS Comput. Biol., 2011, 7 (9), e1002201

Marcos, E.; Crehuet, R.; Bahar, I, On the Conservation of the Slow Conformational Dynamics within the Amino Acid Kinase Family: NAGK the Paradigm, PLoS Comput. Biol, 2010, 6 (4), e1000738

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