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Biomolecules 2019, 9(4), 133; https://doi.org/10.3390/biom9040133

Mutagenesis of DsbAss is Crucial for the Signal Recognition Particle Mechanism in Escherichia coli: Insights from Molecular Dynamics Simulations

1
School of Biological Sciences, Quaid-e-Azam Campus, University of the Punjab, Opp. Sheikh Zaid Hospital, Canal Bank Road, Lahore 54590, Pakistan
2
Faculty of Biological Sciences, Gulab Devi Educational Complex, Lahore, Ferozpur Road, Lahore 54000, Pakistan
3
Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, Medicinal Chemistry, University of Leuven, B-3000 Leuven, Belgium
4
Center for Research in Molecular Medicine, The University of Lahore, Lahore 54000, Pakistan
5
Department Institute of Biological, Environmental and Rural Sciences, Aberystwyth University, Penglais, Aberystwyth, Ceredigion SY23 3FL, UK
6
Institute of Biochemistry and Biotechnology, Quaid-e-Azam Campus, University of the Punjab, Opp. Sheikh Zaid Hospital, Canal Bank Road, Lahore 54590, Pakistan
*
Author to whom correspondence should be addressed.
Received: 2 March 2019 / Revised: 17 March 2019 / Accepted: 20 March 2019 / Published: 3 April 2019
(This article belongs to the Special Issue Protein Dynamics Simulations)
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Abstract

The disulfide bond signal sequence (DsbAss) protein is characterized as an important virulence factor in gram-negative bacteria. This study aimed to analyze the “alanine” alteration in the hydrophobic (H) region of DsbAss and to understand the conformational DsbAss alteration(s) inside the fifty-four homolog (Ffh)-binding groove which were revealed to be crucial for translocation of ovine growth hormone (OGH) to the periplasmic space in Escherichia coli via the secretory (Sec) pathway. An experimental design was used to explore the hydrophobicity and alteration of alanine (Ala) to isoleucine (Ile) in the tripartite structure of DsbAss. As a result, two DsbAss mutants (Ala at positions -11 and -13) with same hydrophobicity of 1.539 led to the conflicting translocation of the active OGH gene. We performed molecular dynamics (MD) simulations and molecular mechanics generalized born surface area (MM-GBSA) binding free energy calculations to examine the interaction energetic and dynamic aspects of DsbAss/signal repetition particle 54 (SRP54) binding, which has a principle role in Escherichia coli Sec pathways. Although both DsbAss mutants retained helicity, the MD simulation analysis evidenced that altering Ala-13 changed the orientation of the signal peptide in the Ffh M binding domain groove, favored more stable interaction energies (MM-GBSA ΔGtotal = −140.62 kcal mol−1), and hampered the process of OGH translocation, while Ala-11 pointed outward due to unstable conformation and less binding energy (ΔGtotal = −124.24 kcal mol−1). Here we report the dynamic behavior of change of “alanine” in the H-domain of DsbAss which affects the process of translocation of OGH, where MD simulation and MM-GBSA can be useful initial tools to investigate the virulence of bacteria. View Full-Text
Keywords: DsbA signal sequence; ovine growth hormone; signal recognition particle system; molecular dynamics simulation; molecular mechanics generalized born surface area DsbA signal sequence; ovine growth hormone; signal recognition particle system; molecular dynamics simulation; molecular mechanics generalized born surface area
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Durrani, F.G.; Gul, R.; Mirza, M.U.; Kaderbhai, N.N.; Froeyen, M.; Saleem, M. Mutagenesis of DsbAss is Crucial for the Signal Recognition Particle Mechanism in Escherichia coli: Insights from Molecular Dynamics Simulations. Biomolecules 2019, 9, 133.

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