Exploring the Cold-Adaptation Mechanism of Serine Hydroxymethyltransferase by Comparative Molecular Dynamics Simulations.

Zhi-Bi Zhang,Guang-Heng Dong,Yun-Xin Fu,Shu-Qun Liu,Yuan-Ling Xia

doi:10.3390/ijms22041781

Abstract

Cold-adapted enzymes feature a lower thermostability and higher catalytic activity compared to their warm-active homologues, which are considered as a consequence of increased flexibility of their molecular structures. The complexity of the (thermo)stability-flexibility-activity relationship makes it difficult to define the strategies and formulate a general theory for enzyme cold adaptation. Here, the psychrophilic serine hydroxymethyltransferase (pSHMT) from Psychromonas ingrahamii and its mesophilic counterpart, mSHMT from Escherichia coli, were subjected to μs-scale multiple-replica molecular dynamics (MD) simulations to explore the cold-adaptation mechanism of the dimeric SHMT. The comparative analyses of MD trajectories reveal that pSHMT exhibits larger structural fluctuations and inter-monomer positional movements, a higher global flexibility, and considerably enhanced local flexibility involving the surface loops and active sites. The largest-amplitude motion mode of pSHMT describes the trends of inter-monomer dissociation and enlargement of the active-site cavity, whereas that of mSHMT characterizes the opposite trends. Based on the comparison of the calculated structural parameters and constructed free energy landscapes (FELs) between the two enzymes, we discuss in-depth the physicochemical principles underlying the stability-flexibility-activity relationships and conclude that (i) pSHMT adopts the global-flexibility mechanism to adapt to the cold environment and, (ii) optimizing the protein-solvent interactions and loosening the inter-monomer association are the main strategies for pSHMT to enhance its flexibility.

Highlights

More than three-quarters of the Earth’s surface is occupied by cold ecosystems, including the Arctic, Antarctic, Alpine regions and deep seas
The cold-adaptation mechanism of serine hydroxymethyltransferase (SHMT) was investigated by performing μs-scale multiple-replica molecular dynamics (MD) simulations on the psychrophilic psychrophilic serine hydroxymethyltransferase (pSHMT) and mesophilic mSHMT followed by a series of comparative analyses in terms of the dynamics, structural properties, and free energy landscapes (FELs)
It can be concluded that pSHMT likely adopts the global-flexibility mechanism to adapt to the cold environment, with the considerably increased local flexibility playing roles in either lowering the activation free energy or modulating the kinetics and thermodynamics of enzyme-substrate interactions

Summary

Introduction

More than three-quarters of the Earth’s surface is occupied by cold ecosystems, including the Arctic, Antarctic, Alpine regions and deep seas. The low thermostability of cold-adapted enzymes should be a consequence of weakening intra-molecular forces, which in turn leads to the enhanced conformational dynamics or flexibility, making it easy to accomplish the conformational changes required for catalysis at low temperatures. It appears that the flexibility of the molecular structure establishes a link between the thermostability and catalytic activity of enzymes, with increased flexibility of the psychrophilic enzyme lowering the thermostability (or structural stability) and maintaining a high catalytic activity at low temperatures [4]. The actual (thermo)stability-flexibility-activation relationships seem to be more complicated than the above description would suggest

Methods

Results

Conclusion