Citrate synthase proteins in extremophilic organisms: Studies within a structure-based model

TL;DR

This study uses a structure-based model to analyze citrate synthase proteins from extremophiles, revealing how stability, flexibility, and motion patterns vary with environmental adaptation and conformational states.

Contribution

It demonstrates that native amino acid contact patterns are key to understanding stability and dynamics differences among extremophilic and mesophilic citrate synthases.

Findings

Thermophilic proteins are more thermodynamically stable than mesophilic and cryophilic counterparts.

Stability correlates with amino acid contact coordination and structural compactness.

Distinct fluctuation and motion patterns are observed between open and closed conformations.

Abstract

We study four citrate synthase homodimeric proteins within a structure-based coarse-grained model. Two of these proteins come from thermophilic bacteria, one from a cryophilic bacterium and one from a mesophilic organism; three are in the closed and two in the open conformations. Even though the proteins belong to the same fold, the model distinguishes the properties of these proteins in a way which is consistent with experiments. For instance, the thermophilic proteins are more stable thermodynamically than their mesophilic and cryophilic homologues, which we observe both in the magnitude of thermal fluctuations near the native state and in the kinetics of thermal unfolding. The level of stability correlates with the average coordination number for amino acids contacts and with the degree of structural compactness. The pattern of positional fluctuations along the sequence in the closed conformation is different than in the open conformation, including within the active site. The modes of correlated and anticorrelated movements of pairs of amino acids forming the active site are very different in the open and closed conformations. Taken together, our results show that the precise location of amino acid contacts in the native structure appears to be a critical element in explaining the similarities and differences in the thermodynamic properties, local flexibility and collective motions of the different forms of the enzyme.