Infection Dynamics of ATG8 in Leishmania: Balancing Autophagy for Therapeutics
Abstract
:1. Introduction
2. Methodology
2.1. Phylogenetic Tree Construction for Sequential Analysis
2.1.1. Sequence Acquisition
2.1.2. Multiple Sequence Alignment (MSA)
2.1.3. Phylogenetic Tree Construction
2.2. Statistical Coupling Analysis (SCA) for Positional Conservedness Analysis
2.3. Structural and Functional Residue Validation
2.4. Effect of Conserved Amino Acid Substitution on Protein
2.4.1. SDM (Site Directed Mutator)
2.4.2. PROVEAN (Protein Variation Effect Analyzer)
2.4.3. SODA
2.4.4. Arpeggio
2.5. Structure Prediction, Validation, and Interaction studies
2.6. Virtual Screening
2.7. Molecular Docking
2.8. Molecular Dynamics Simulation
3. Results
3.1. Conservedness Analysis of ATG Proteins
3.1.1. Sequential Conservedness Analysis
3.1.2. Positional Conservedness Analysis
3.2. Structural and Functional Residue Validation
3.3. Effect of Conserved Amino Acid Substitution on Protein
3.4. Computational Structure Prediction, Validation and Molecular Dynamics Simulation
3.5. Molecular Dynamics Simulation of Proteins
3.6. Protein-Protein interactions
3.7. ATG8 Can Be a Novel Target for Therapeutics against Leishmaniasis
3.8. Virtual Screening of Thiabendazole Derivatives against ATG8
3.9. Molecular Docking and Molecular Dynamics Simulation (MDS)
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
Abbreviations
ATG | Autophagy Related Proteins |
ULK1 | unc-51-like kinase 1 |
PI3K | phosphatidylinositol (PI) 3-kinase complex |
VPS | Vacuolar Protein Sorting |
WIPI | WD repeat domain phosphoinositide interacting protein 2 |
DFCP1 | Double FYVE containing protein 1 |
LC3 | Microtubule-associated proteins 1A/1B light chain 3 |
SCA | Statistical Coupling Analysis |
SDM | Site Directed Mutator |
PROVEAN | Protein Variation Effect Analyzer |
SCA | Statistical Coupling Analysis |
PE | Phosphatidylethanolamine |
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Amino Acid Substitution | ΔΔG | Stability | PROVEAN Score | Impact on Protein | SODA Score | Solubility | |
---|---|---|---|---|---|---|---|
ATG8 | R71T | −1.94 | Decrease | −5.825 | Deleterious | −14.878 | Less Soluble |
P56E | −1.07 | Decrease | −7.694 | Deleterious | −2.13 | Less Soluble | |
R18P | −3.81 | Decrease | −6.641 | Deleterious | −1.685 | Less Soluble | |
ATG5 | P110C | 0.29 | Increase | −6.250 | Deleterious | −50.412 | Less Soluble |
P89K | −1.04 | Decrease | −7.000 | Deleterious | −2.053 | Less Soluble | |
D47P | −0.74 | Decrease | −7.000 | Deleterious | −2.279 | Less Soluble | |
ATG12 | P41K | −1.04 | Decrease | −3.098 | Deleterious | −60.883 | Less Soluble |
P152N | 0.91 | Increase | −6.968 | Deleterious | −13.018 | Less Soluble | |
E178T | −2.00 | Decrease | −5.600 | Deleterious | −15.209 | Less Soluble | |
N179R | −1.99 | Decrease | −5.200 | Deleterious | −1.375 | Less Soluble | |
ATG4.1 | D133T | 0.03 | Increase | −6.980 | Deleterious | −12.363 | Less Soluble |
P213G | −1.13 | Decrease | −4.467 | Deleterious | −213.32 | Less Soluble | |
G244I | −2.29 | Decrease | −10.00 | Deleterious | −17.447 | Less Soluble | |
P265K | −0.88 | Decrease | −7.987 | Deleterious | −11.794 | Less Soluble |
ATG4.1 | ATG8 | Interactions | |
---|---|---|---|
Interacting Residues | Arg276 | Val88 | Hydrogen Bond |
Arg276 | Pro89 | Hydrogen Bond | |
Arg73 | Glu116 | Hydrogen Bond and Salt Bridge | |
Arg73 | Asn117 | Hydrogen Bond | |
Cys75 | Gly120 | Hydrogen Bond | |
ATG5 | ATG12 | Interactions | |
Interacting Residues | Glu125 | Arg186 | Hydrogen Bond and Salt Bridge |
Pro269 | Lys29 | Hydrogen Bond | |
Lys131 | Glu191 | Hydrogen Bond and Salt Bridge | |
Arg146 | Glu191 | Hydrogen Bond and Salt Bridge | |
Arg146 | Glu45 | Hydrogen Bond and Salt Bridge | |
Glu128 | Asp184 | Hydrogen Bond | |
Lys127 | Glu22 | Hydrogen Bond and Salt Bridge | |
Tyr115 | Gly182 | Hydrogen Bond | |
Gln175 | His80 | Hydrogen Bond | |
Gln175 | Arg79 | Hydrogen Bond |
Derivatives | IUPAC Name | Structure of Derivative | Binding Energy | Molecular Weight | LogP | H-Donor | H-Acceptor |
---|---|---|---|---|---|---|---|
TB98 | N-(1H-Benzimidazol-2-yl)-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridin-2-amine | −8.1 | 271.34 | 2.2 | 3 | 5 | |
TB612 | 1-[3-(1H-Benzimidazol-2-yl)propyl]-2-methyl-3-[[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl]guanidine | −8.4 | 396.4 | 2.9 | 3 | 7 | |
TB620 | 2-[3-(1H-Benzimidazol-2-yl)propyl]-1-ethyl-3-[2-[4-(trifluoromethyl)-1,3-thiazol-2-yl]ethyl]guanidine | −8.6 | 424.5 | 3.7 | 3 | 7 |
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Guhe, V.; Anjum, F.; Shafie, A.; Hassan, M.I.; Pasupuleti, V.R.; Singh, S. Infection Dynamics of ATG8 in Leishmania: Balancing Autophagy for Therapeutics. Molecules 2022, 27, 3142. https://doi.org/10.3390/molecules27103142
Guhe V, Anjum F, Shafie A, Hassan MI, Pasupuleti VR, Singh S. Infection Dynamics of ATG8 in Leishmania: Balancing Autophagy for Therapeutics. Molecules. 2022; 27(10):3142. https://doi.org/10.3390/molecules27103142
Chicago/Turabian StyleGuhe, Vrushali, Farah Anjum, Alaa Shafie, Md Imtaiyaz Hassan, Visweswara Rao Pasupuleti, and Shailza Singh. 2022. "Infection Dynamics of ATG8 in Leishmania: Balancing Autophagy for Therapeutics" Molecules 27, no. 10: 3142. https://doi.org/10.3390/molecules27103142