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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

(a) the wild type with SHV in the left panel and its neighbors in the wild type are shown (b) the S130G mutant in the right panel and its neighbors in the mutant type its neighbors in the wild type are shown.
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pone-0112456-g002: (a) the wild type with SHV in the left panel and its neighbors in the wild type are shown (b) the S130G mutant in the right panel and its neighbors in the mutant type its neighbors in the wild type are shown.

Mentions: Hydrogen bonds, which are considered to be the key constituents of biomolecular structures [31], participate in the formation of secondary [32], tertiary and quaternary structures [33] of proteins. The drift in structural property of S130G can result in loss of hydrogen bonds and disturb correct folding and could have a significant impact on the structural integrity. This mutation also cause disturbance in the interactions with other molecules or other parts of the protein. Figure 2a illustrates the distance between native S130, neighboring residues A126 and K234. The native S130 maintains the distance range of 2.9 Å −3.2 Å between neighboring residues K234 and A126 respectively, while in mutant (S130G) substitution of glycine, the distance between mutant G130 and its neighboring residue, A126 (distance 3.3 Å) (Figure 2b). Mutation results in the changes in local environment of SHV and enhance in the modification of residues distances. As can be seen from figure, the wt residue, S130, is involved in several hydrogen bonds, which are absent in the mutant.


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)

(a) the wild type with SHV in the left panel and its neighbors in the wild type are shown (b) the S130G mutant in the right panel and its neighbors in the mutant type its neighbors in the wild type are shown.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0112456-g002: (a) the wild type with SHV in the left panel and its neighbors in the wild type are shown (b) the S130G mutant in the right panel and its neighbors in the mutant type its neighbors in the wild type are shown.
Mentions: Hydrogen bonds, which are considered to be the key constituents of biomolecular structures [31], participate in the formation of secondary [32], tertiary and quaternary structures [33] of proteins. The drift in structural property of S130G can result in loss of hydrogen bonds and disturb correct folding and could have a significant impact on the structural integrity. This mutation also cause disturbance in the interactions with other molecules or other parts of the protein. Figure 2a illustrates the distance between native S130, neighboring residues A126 and K234. The native S130 maintains the distance range of 2.9 Å −3.2 Å between neighboring residues K234 and A126 respectively, while in mutant (S130G) substitution of glycine, the distance between mutant G130 and its neighboring residue, A126 (distance 3.3 Å) (Figure 2b). Mutation results in the changes in local environment of SHV and enhance in the modification of residues distances. As can be seen from figure, the wt residue, S130, is involved in several hydrogen bonds, which are absent in the mutant.

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