Recent Advances in Free Energy Calculations with a Combination of Molecular Mechanics and Continuum Models

Wang, Junmei; Hou, Tingjun; Xu, Xiaojie

doi:10.2174/157340906778226454

Cited by 326 publications

(273 citation statements)

References 53 publications

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“…This result is in agreement with the previous studies which showed that MM/GBSA method is often useful to refine the binding scores resulted from docking-based virtual screening [15]. Nevertheless, a better conformational sampling for MM/GBSA method should be able to improve the accuracy of binding energy calculation.…”

Section: Discussionsupporting

confidence: 92%

In Silico Study of Cryo-Em Structures of Antigen-Antibody Complex of Chikungunya for the Development of Diagnostic Agent

Subroto

Nuwarda

Baroroh

et al. 2017

Asian J Pharm Clin Res

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Objective: Despite the availability of the commercial rapid tests of chikungunya, the difference of pathogen's genotypes amongst different countries has created some causes for concern. It is found that the sensitivity of the current chikungunya rapid tests on Asian strain was only 20.5%, as compared to 90.3% when tested on the African phylogroup. Therefore, the development of diagnostics that is specific for the current strain circulating in the country is important to be done. The cryo-electron microscopy (cryo-EM) structures of antigen-antibody complex can be used as an insightful structural basis to the development of the tailored antibody for diagnostics purposes. However, cryo-EM structures usually were resolved in low resolution, thus some sterical clashes between residues are expected. This work aims to refine the cryo-EM structures of E1-E2 of chikungunya virus in complex with antibody using molecular mechanics method, to calculate the binding energy of antigen-antibody complex, and to compare it with the experimental results. Methods:The cryo-EM structures were refined in vacuo by short minimization scheme using AMBER 14. The binding energies were calculated using FireDock and Molecular Mechanics Generalized Boltzmann Surface Area methods. Results:The results showed that the direct calculation of binding energies of cryo-EM structures reflected high repulsive forces. While the calculation on the refined structure showed lower binding energies. Visual inspections on the complex structures also indicated that the refined structures showed better interactions. Conclusion:The refinement of cryo-EM structures should be useful to gain more insight into the binding mode of interactions between antigenic protein and antibody, at the atomic level.

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Section: Discussionsupporting

confidence: 92%

In Silico Study of Cryo-Em Structures of Antigen-Antibody Complex of Chikungunya for the Development of Diagnostic Agent

Subroto

Nuwarda

Baroroh

et al. 2017

Asian J Pharm Clin Res

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“…39 Binding free energy approaches like MM/PBSA and MM/GBSA are computationally more efficient 36,44,45 than the theoretically rigorous approaches such as thermodynamic integration 46 and free energy perturbation. [47][48][49] In this study, the binding free energies were estimated using mmpbsa program in AMBER.…”

Section: Resultsmentioning

confidence: 99%

Theoretical Characterization of Binding Mode of Organosilicon Inhibitor with p38: Docking, MD Simulation and MM/GBSA Free Energy Approach

Gadhe¹,

Balupuri²,

Kothandan³

et al. 2014

Bulletin of the Korean Chemical Society

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P38 mitogen activated protein (MAP) kinase is an important anti-inflammatory drug target, which can be activated by responding to various stimuli such as stress and immune response. Based on the conformation of the conserved DFG loop (in or out), binding inhibitors are termed as type-I and II. Type-I inhibitors are ATP competitive, whereas type-II inhibitors bind in DFG-out conformation of allosteric pocket. It remains unclear that how these allosteric inhibitors stabilize the DFG-out conformation and interact. Organosilicon compounds provide unusual opportunity to enhance potency and diversity of drug molecules due to their low toxicity. However, very few examples have been reported to utilize this property. In this regard, we performed docking of an inhibitor (BIRB) and its silicon analog (Si-BIRB) in an allosteric binding pocket of p38. Further, molecular dynamics (MD) simulations were performed to study the dynamic behavior of the simulated complexes. The difference in the biological activity and mechanism of action of the simulated inhibitors could be explained based on the molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy per residue decomposition. MM/GBSA showed that biological activities were related with calculated binding free energy of inhibitors. Analyses of the per-residue decomposed energy indicated that van der Waals and non-polar interactions were predominant in the ligand-protein interactions. Further, crucial residues identified for hydrogen bond, salt bridge and hydrophobic interactions were Tyr35, Lys53, Glu71, Leu74, Leu75, Ile84, Met109, Leu167, Asp168 and Phe169. Our results indicate that stronger hydrophobic interaction of Si-BIRB with the binding site residues could be responsible for its greater binding affinity compared with BIRB.

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“…Each of the TPO 201-500 -ATD complexes was subjected to Molecular Dynamics simulation to study its stabilizing properties. In addition, PoissonBoltzmann and generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) [47][48][49][50][51] techniques were endorsed to calculate binding free energies of MMZ and PTU to TPO 201-500 . PBTOT for TPO 201-500 -MMZ and TPO 201-500 -PTU was -11.05 and -14.02 kcal mol-1 while GBTOT for TPO 201-500 -MMZ and TPO 201-500 -PTU was found -9.43 and -15.47 kcal mol-1 respectively, which put forth the inhibitors to have high affinity to TPO 201-500 in the dynamic system.…”

Section: Introductionmentioning

confidence: 99%

Comparative Study on the Binding Affinity of Methimazole and Propylthiouracil to Thyroid Peroxidase as an Anti-Thyroid Drug: An Insilico Approach

Pradhan¹,

Sarma²,

Bharadwaz³

et al. 2017

J Mol Imaging Dynam

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Graves' disease (GD), an autoimmune disorder, scars majority of women worldwide, causing hyperthyroidism, Graves's ophthalmopathy and goitre. Thyroid Peroxidase (TPO) is an active target of anti-thyroid drugs, Methimazole and Propylthiouracil, which inhibit the enzyme function of catalysing the thyroid hormones synthesis. Most of the protein-drug interaction studies so far have been focussed mainly at in vivo level, or by using Myeloperoxidase and Lactose peroxidases as TPO surrogates for the same. This makes the molecular interaction of TPO with the drugs crucial to understand. In this study, we used the molecular dynamics (MD) to study the molecular interaction differences between TPO 201-500 and both drugs. The binding free energy calculation done using Molecular Mechanics Poisson-Boltzmann (MM-PBSA) and generalized Born and surface area continuum solvation (GBSA) results indicated that both drugs bind strongly to TPO 201-500 , with Propylthiouracil having slightly higher binding energy than Methimazole. We found that both drugs interacted with the residues-Asp238, His239, Phe243, Thr487 and His494 through hydrophobic interactions and formed stable hydrogen bonds with residue Arg491 of TPO 201-500 . Since both drugs engage residues-Asp238, His239 and His494 which falls within the proximal heme binding site and catalytic site of TPO 201-500 , we can conclude that these drugs may be conducive in inhibiting the enzymatic activity of TPO 201-500 .

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Recent Advances in Free Energy Calculations with a Combination of Molecular Mechanics and Continuum Models

Cited by 326 publications

References 53 publications

In Silico Study of Cryo-Em Structures of Antigen-Antibody Complex of Chikungunya for the Development of Diagnostic Agent

In Silico Study of Cryo-Em Structures of Antigen-Antibody Complex of Chikungunya for the Development of Diagnostic Agent

Theoretical Characterization of Binding Mode of Organosilicon Inhibitor with p38: Docking, MD Simulation and MM/GBSA Free Energy Approach

Comparative Study on the Binding Affinity of Methimazole and Propylthiouracil to Thyroid Peroxidase as an Anti-Thyroid Drug: An Insilico Approach

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