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Insight into the effect of inhibitor resistant S130G mutant on physico-chemical properties of SHV type beta-lactamase: a molecular dynamics study.

Baig MH, Sudhakar DR, Kalaiarasan P, Subbarao N, Wadhawa G, Lohani M, Khan MK, Khan AU - PLoS ONE (2014)

Bottom Line: In the present study, we have analyzed the effect of inhibitor resistant S130G point mutation of SHV type Class-A β-lactamase using molecular dynamics and other in silico approaches.The results clearly suggest notable loss in the stability of S130G mutant that may further lead to decrease in substrate specificity of SHV.Molecular docking further indicates that S130G mutation decreases the binding affinity of all the three inhibitors in clinical practice.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India; Department of Biosciences, Integral University, Lucknow, India.

ABSTRACT
Bacterial resistance is a serious threat to human health. The production of β-lactamase, which inactivates β-lactams is most common cause of resistance to the β-lactam antibiotics. The Class A enzymes are most frequently encountered among the four β-lactamases in the clinic isolates. Mutations in class A β-lactamases play a crucial role in substrate and inhibitor specificity. SHV and TEM type are known to be most common class A β-lactamases. In the present study, we have analyzed the effect of inhibitor resistant S130G point mutation of SHV type Class-A β-lactamase using molecular dynamics and other in silico approaches. Our study involved the use of different in silico methods to investigate the affect of S130G point mutation on the major physico-chemical properties of SHV type class A β-lactamase. We have used molecular dynamics approach to compare the dynamic behaviour of native and S130G mutant form of SHV β-lactamase by analyzing different properties like root mean square deviation (RMSD), H-bond, Radius of gyration (Rg) and RMS fluctuation of mutation. The results clearly suggest notable loss in the stability of S130G mutant that may further lead to decrease in substrate specificity of SHV. Molecular docking further indicates that S130G mutation decreases the binding affinity of all the three inhibitors in clinical practice.

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Related in: MedlinePlus

Backbone RMSDs are shown for native and S130 mutant SHV β-lactamase at 300 K, black color indicate native SHV, point mutant form S130G SHV β-lactamase shown in red.
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pone-0112456-g003: Backbone RMSDs are shown for native and S130 mutant SHV β-lactamase at 300 K, black color indicate native SHV, point mutant form S130G SHV β-lactamase shown in red.

Mentions: In the present study, comparative molecular dynamics simulations were performed in order to study the difference in protein dynamics of wild type and its mutant. The main chain root mean square deviations were calculated for the trajectories of the wild and mutated SHV. The RMSD was calculated using the trajectory file for backbone after least square fit to C-alpha using “g_rms” tool. It is evident that the wt (3D4F) and mutant structure (1TDG) remain close at their starting conformation till 2000 ps which results in a backbone RMSD of about ∼0.2 nm (Figure 3). Between ranges of 2000–5000 ps, structure of SHV wild type attained a maximum RMSD value of ∼0.23 nm while the S130G mutant attained a highest deviation of ∼0.27 nm. From 5000 ps till 9000 ps, a slight deviation in RMSD was also observed, where mutant S130G retained a large deviation from wt, with a maximum RMSD of ∼0.27 nm around 9000 ps. The RMSD of both the structures (wt and mutant) remained constant throughout the rest of time period.


Insight into the effect of inhibitor resistant S130G mutant on physico-chemical properties of SHV type beta-lactamase: a molecular dynamics study.

Baig MH, Sudhakar DR, Kalaiarasan P, Subbarao N, Wadhawa G, Lohani M, Khan MK, Khan AU - PLoS ONE (2014)

Backbone RMSDs are shown for native and S130 mutant SHV β-lactamase at 300 K, black color indicate native SHV, point mutant form S130G SHV β-lactamase shown in red.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4257546&req=5

pone-0112456-g003: Backbone RMSDs are shown for native and S130 mutant SHV β-lactamase at 300 K, black color indicate native SHV, point mutant form S130G SHV β-lactamase shown in red.
Mentions: In the present study, comparative molecular dynamics simulations were performed in order to study the difference in protein dynamics of wild type and its mutant. The main chain root mean square deviations were calculated for the trajectories of the wild and mutated SHV. The RMSD was calculated using the trajectory file for backbone after least square fit to C-alpha using “g_rms” tool. It is evident that the wt (3D4F) and mutant structure (1TDG) remain close at their starting conformation till 2000 ps which results in a backbone RMSD of about ∼0.2 nm (Figure 3). Between ranges of 2000–5000 ps, structure of SHV wild type attained a maximum RMSD value of ∼0.23 nm while the S130G mutant attained a highest deviation of ∼0.27 nm. From 5000 ps till 9000 ps, a slight deviation in RMSD was also observed, where mutant S130G retained a large deviation from wt, with a maximum RMSD of ∼0.27 nm around 9000 ps. The RMSD of both the structures (wt and mutant) remained constant throughout the rest of time period.

Bottom Line: In the present study, we have analyzed the effect of inhibitor resistant S130G point mutation of SHV type Class-A β-lactamase using molecular dynamics and other in silico approaches.The results clearly suggest notable loss in the stability of S130G mutant that may further lead to decrease in substrate specificity of SHV.Molecular docking further indicates that S130G mutation decreases the binding affinity of all the three inhibitors in clinical practice.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India; Department of Biosciences, Integral University, Lucknow, India.

ABSTRACT
Bacterial resistance is a serious threat to human health. The production of β-lactamase, which inactivates β-lactams is most common cause of resistance to the β-lactam antibiotics. The Class A enzymes are most frequently encountered among the four β-lactamases in the clinic isolates. Mutations in class A β-lactamases play a crucial role in substrate and inhibitor specificity. SHV and TEM type are known to be most common class A β-lactamases. In the present study, we have analyzed the effect of inhibitor resistant S130G point mutation of SHV type Class-A β-lactamase using molecular dynamics and other in silico approaches. Our study involved the use of different in silico methods to investigate the affect of S130G point mutation on the major physico-chemical properties of SHV type class A β-lactamase. We have used molecular dynamics approach to compare the dynamic behaviour of native and S130G mutant form of SHV β-lactamase by analyzing different properties like root mean square deviation (RMSD), H-bond, Radius of gyration (Rg) and RMS fluctuation of mutation. The results clearly suggest notable loss in the stability of S130G mutant that may further lead to decrease in substrate specificity of SHV. Molecular docking further indicates that S130G mutation decreases the binding affinity of all the three inhibitors in clinical practice.

Show MeSH
Related in: MedlinePlus