Thermal Stability of Globins: Implications of Flexibility and Heme Coordination Studied by Molecular Dynamics Simulations

Abstract

Proteins are sensitive to temperature, and abrupt changes in the normal temperature conditions can have a profound impact on both structure and function, leading to protein unfolding. However, the adaptation of certain organisms to extreme conditions raises questions about the structural features that permit the structure and function of proteins to be preserved under these adverse conditions. To gain insight into the molecular basis of protein thermostability in the globin family, we have examined three representative examples: human neuroglobin, horse heart myoglobin, and Drosophila hemoglobin, which differ in their melting temperatures and coordination states of the heme iron in the absence of external ligands. In order to elucidate the possible mechanisms that govern the thermostability of these proteins, microsecond-scale classical molecular dynamics simulations were performed at different temperatures. Structural fluctuations and essential dynamics were analyzed, indicating that the flexibility of the CD region, which includes the two short C and D helixes and the connecting CD loop, is directly related to the thermostability. We observed that a larger inherent flexibility of the protein produces higher thermostability, probably concentrating the thermal fluctuations observed at high temperature in flexible regions, preventing unfolding. Globally, the results of this work improve our understanding of thermostability in the globin family.

Enhancing thermostability by modifying flexible surface loops in an evolved high‐redox potential laccase

“…That is, loops that do not interact with heavy structural secondary structure motifs and that are partly protruding from the protein. This is the case of myoglobin and it fits well also with the Ser356Asn mutation of the present study.…”

“…Thus, our data seems to indicate the possible reorganization of this region due to the loss of a H‐bond with the neighboring Leu352, Figure c,d. While the rigidification of flexible loops is beneficial for thermostability, only a few recent studies are addressing that the gain in flexibility of loose loops, largely exposed to the solvent, may increase the enzyme capability to adapt to high temperatures . From the few data available, it seems like these flexible loops should be partly independent.…”

Investigation of the Effect of Temperature on the Structure of SARS-CoV-2 Spike Protein by Molecular Dynamics Simulations

“…Temperature is a very significant variable parameter for proteins because proteins respond differently in high and low temperature conditions. Many proteins have high thermal stability while others can unfold or even denature at high temperatures (Dong et al, 2018;Julió Plana et al, 2019). Experimental studies by Xiong et al (2020), where they generated a mutated Spike protein that exhibited high level of thermal stability.…”

Computational Exploration of Anti-cancer Potential of Flavonoids against Cyclin-Dependent Kinase 8: An In Silico Molecular Docking and Dynamic Approach

“…Further, the MD simulation study of the targeted empty protein structure and the protein–ligand complex with the highest negative binding affinity was carried out in varied temperature conditions to determine the effect of temperature on the structural rearrangement and the unfolding of the protein. − Previously, Rocco et al performed a temperature-dependent MD simulation of protein structure to determine the unfolding processes of the simulated structure . Similarly, Rath and Kumar studied the effect of temperature on the behavior of protein structure under an MD simulation study .…”