On the Thermal Stability of O⁶-Methylguanine-DNA Methyltransferase from Archaeon Pyrococcus kodakaraensis by Molecular Dynamics Simulations

Abstract

We have employed molecular dynamics simulations to analyze the thermal stability of the O 6 -methylguanine-DNA methyltransferase (MGMT) protein, both hyperthermophilic archaeon Pyrococcus kodakaraensis (Pk-MGMT) and its mesophilic homologue pair, obtained from enterobacterium Escherichia coli (AdaC). This theoretical study was done at three different temperatures: 302, 371, and 450 K. The molecular dynamics has been performed in explicit aqueous solvent during a period of time of 95 ns, including periodic boundary conditions and constant pressure. The same procedure has been used for both proteins, and each simulation has been carried out by triplicate. Hence, we performed 18 simulations. In this way, we have done different analyses to explore the factors that may affect the thermal stability of Pk-MGMT. The structural behavior was analyzed using indicators such as root-mean-square deviation, radius of gyration, solvent-accessible surface area, hydrogen bonds, native contacts, secondary structure, and salt bridge formation. The results showed that when the temperature increases, the global atomic fluctuations increase too, which suggests that both proteins lose thermal stability, but as expected, this fact is highlighted in AdaC. Moreover, the contacts of the native state in AdaC are considerably lower than those found in Pk-MGMT at 450 K. Also, the structural studies showed that conserved and nonconserved salt bridges kept close contacts with the Pk-MGMT protein at high temperatures. These interaction types act as molecular staples and are mainly responsible to provide thermostability to the hyperthermophilic protein.

Ordered‐domain unfolding of thermophilic isolated β subunit ATP synthase

“…It can be inferred that this structural arrangement acts as a seed of Tβ stability and as a template for the refolding processes. This fact is in accordance with the literature since there is a tendency indicating that α‐helix SS has lower energetic barriers in comparison to their counterpart β‐sheets (López‐Chávez et al, 2020; Rahban et al, 2022; Vijayakumar et al, 1993; Yang et al, 1996; Yang & Honig, 1995a, 1995b).…”

“…Accessible solvent area: the probe rolling algorithm (Lee & Richards, 1971) implemented in the FreeSASA software (Mitternacht, 2016) was used to calculate structural ASA. A test sphere with a 1.4 Å radius and 100 slices were used for the FreeSASA analysis.…”

Molecular Insights into the Enhanced Activity and/or Thermostability of PET Hydrolase by D186 Mutations

“…Molecules 2024, 29, 1338 10 two regions allow the enzyme to maintain its catalytic activity at high temperatures analysis of mobility and structural fluctuation of PETase WT and its variants by MDLo also confirmed the results mentioned above (Figure S9). The hydrogen bonding was then analyzed as hydrogen bonds play an importan in protein folding and thermostability [55]. It was reported that H186 could promot water-mediated hydrogen bond formation between E121 and N172 in PETase S121E/D186H [17], or H186 could form a water-mediated hydrogen-bonding network with E121 N172 in PETase S121E/D186H/R280A/R224Q/N233K [21].…”

Molecular Dynamics Simulations of HPr Proteins from a Thermophilic and a Mesophilic Organism: A Comparative Thermal Study

“…In addition to this aspect, there is an intrinsic and fundamental interest to understand at a molecular level the contribution of each non-covalent interaction to the thermal stability of such biomolecules. Different computational tools have been used for this purpose, in particular, molecular dynamics (MD) simulation methods have provided relevant information about these interactions, as has been reported in the literature [2,[9][10][11][12][13][14][15][16]]. An interesting strategy consists of directly comparing structural and physicochemical behaviors between homologous proteins, for example, a thermophilic protein and its mesophilic counterpart.…”

“…An interesting strategy consists of directly comparing structural and physicochemical behaviors between homologous proteins, for example, a thermophilic protein and its mesophilic counterpart. Thus, MD approaches have commonly shown that the thermophilic proteins increase their non-covalent interactions, reduce the number of charged residues on the surface, and maintain the structure together and packed [11][12][13][14][15][16].…”