Exploring Protein Stability by Comparative Molecular Dynamics Simulations of Homologous Hyperthermophilic, Mesophilic, and Psychrophilic Proteins

Abstract

In the present studies, we analyzed the influence of temperature on the stability and dynamics of the α subunit of tryptophan synthase (TRPS) from hyperthermophilic, mesophilic, and psychrophilic homologues at different temperatures by molecular dynamics simulations. Employing different indicators such as root-mean-square deviations, root-mean-square fluctuations, principal component analysis, and free energy landscapes, this study manifests the diverse behavior of these homologues with changes in temperature. Especially, an enhancement in the collective motions, classified as representative motions, is observed at high temperature. Similarly, the criterion for the selection of electrostatic interactions in terms of their life span (duty cycle) has indeed helped in identifying the short- and long-lived electrostatic interactions and how they affect the protein's overall stability at different temperatures. Rigidity and flexibility patterns of the homologous proteins are examined using FIRST software along with the calculation of duty cycles with various threshold limits at different temperatures. Rigid cluster decomposition in TRPS of psychrophilic, mesophilic, and hyperthermophilic origin identifies the flexible and rigid regions in the protein. Early loss of rigidity is observed in mesophilic TRPS via loss of contact between the major fragments of the protein compared with the other homologues. In spite of the high similarity of their three-dimensional structures, the overall responses of the three proteins to varying temperatures are significantly different.

Endoplasmic Reticulum and Lysosomal Quality Control of Four Nonsense Mutants of Iduronate 2-Sulfatase Linked to Hunter's Syndrome

“…1C). To this end, we monitored structural quantities such as RMSF and RMSD to assess protein stability and deviation from the reference IDS WT crystal structure (Khan et al, 2016;Demydchuk et al, 2017;Dong et al, 2018). The larger RMSF and RMSD values for IDS W337X (Fig.…”

Molecular dynamics suggests antiviral compounds active against Dengue Virus show similar binding patterns to Zika Virus proteins

“…Previous studies have suggested that the activity of enzymes is directly correlated with the flexibility of their active site, connecting rigidity with loss of function in most cases (Khan et al, 2016;Rashin et al, 2010).…”

“…Previous studies have suggested that the activity of enzymes is directly correlated with the flexibility of their active site, connecting rigidity with loss of function in most cases(Khan et al, 2016;Rashin et al, 2010). Ligand interactions with its target site increases side-chain rearrangements and may also contribute to conformational changes otherwise bound to enzymatic processes.…”

Identification of new benzamide inhibitor againstα-subunit of tryptophan synthase fromMycobacterium tuberculosisthrough structure-based virtual screening, anti-tuberculosis activity and molecular dynamics simulations

“…The loop6 and loop2 has been reported important for catalytic activity of α-subunit of TRPS that facilitate ligand retention as well as its interaction inside the binding pocket (Khan, Farooq, & Kurnikova, 2016). The RMSF analysis of benzamide inhibitor protein complex showed major fluctuations in loop6 region that help in orientation of active site in order to retain ligand inside binding pocket as depicted in Figure 6(A).…”