Exploring the Molecular Basis of dsRNA Recognition by Mss116p Using Molecular Dynamics Simulations and Free-Energy Calculations

Xue, Qiao; Zhang, Jilong; Zheng, Qing‐Chuan; Cui, Ying; Lin, Cheng Huang; Chu, Wen-Ting; Zhang, Hongxing

doi:10.1021/la402354r

Cited by 21 publications

(19 citation statements)

References 50 publications

(92 reference statements)

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“…In our results of MM‐GBSA, the binding free energy of MARV VP35 to dsRNA is only −18.17 kcal/mol. Compared with some other protein–dsRNA systems, binding free energies calculated by MM‐GBSA, the binding affinity of VP35 to dsRNA is low . This is consistent with the biological experimental result of VP35.…”

Section: Discussionsupporting

confidence: 83%

“…In recent years, molecular dynamics (MD) simulations combined with binding free‐energy calculations has been proven to be successful in exploring protein–protein, protein–DNA, and protein–RNA interactions . This method can provide not only plentiful dynamic structural information about the protein–RNA complex but also abundant energy information . Detailed information would contribute to further understanding of the essence of protein–RNA interaction and demonstrate the origin of the binding affinity.…”

Section: Introductionmentioning

confidence: 99%

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Exploring the mechanism how Marburg virus VP35 recognizes and binds dsRNA by molecular dynamics simulations and free energy calculations

et al. 2014

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Filoviruses often cause terrible infectious disease which has not been successfully dealt with pharmacologically. All filoviruses encode a unique protein termed VP35 which can mask doubled-stranded RNA to deactivate interferon. The interface of VP35-dsRNA would be a feasible target for structure-based antiviral agent design. To explore the essence of VP35-dsRNA interaction, molecular dynamics simulation combined with MM-GBSA calculations were performed on Marburg virus VP35-dsRNA complex and several mutational complexes. The energetic analysis indicates that nonpolar interactions provide the main driving force for the binding process. Although the intermolecular electrostatic interactions play important roles in VP35-dsRNA interaction, the whole polar interactions are unfavorable for binding which result in a low binding affinity. Compared with wild type VP35, the studied mutants F228A, R271A, and K298A have obviously reduced binding free energies with dsRNA reflecting in the reduction of polar or nonpolar interactions. The results also indicate that the loss of binding affinity for one dsRNA strand would abolish the total binding affinity. Three important residues Arg271, Arg294, and Lys298 which makes the largest contribution for binding in VP35 lose their binding affinity significantly in mutants. The uncovering of VP35-dsRNA recognition mechanism will provide some insights for development of antiviral drug.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Exploring the mechanism how Marburg virus VP35 recognizes and binds dsRNA by molecular dynamics simulations and free energy calculations

et al. 2014

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“…The MM‐GB/SA methods implemented in AMBER 11 was applied to calculate the binding free energy between the ligand and the enzyme . The binding free energy (Δ G bind ) in MM‐GB/SA between a ligand (L) and a receptor (R) to form a complex RL was calculated as

Δ G_{bind} = G_{complex} - true(G_{receptor} + G_{ligand} true)

G = E_{MM} + G_{sol} - T S

E_{MM} = E_{int} + E_{ele} + E_{vdw}

G_{sol} = G_{GB} + G_{SA}

…”

Section: Methodsmentioning

confidence: 99%

Molecular basis of the recognition of arachidonic acid by cytochrome P450 2E1 along major access tunnel

et al. 2014

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Cytochrome P450 2E1 is widely known for its ability to oxidize both low molecular weight xenobiotics and endogenous fatty acids (e.g., arachidonic acid (AA)). In this study, we investigated the structural features of the AA-bound CYP2E1 complex utilizing molecular dynamics (MD) and found that the distinct binding modes for both AA and fatty acid analog are conserved. Moreover, multiple random acceleration MD simulations and steered MD simulations uncovered the most possible tunnel for fatty acids. The main attractions are derived from three key residues, His107, Ala108, and His109, whose side chains reorient to keep ligands bound via hydrogen bonds during the initial unbinding process. More importantly, based on the calculated binding free energy results, we hypothesize that the hydrogen bonds between the receptor and the ligand are the most important contributors involved in the binding affinity. Thus, it is inferred that the hydrogen bonds between these three residues and the ligand may help offer insights into the structural basis of the different ligand egress mechanisms for fatty acids and small weight compounds. Our investigation provides detailed atomistic insights into the structural features of human CYP2E1-fatty acid complex structures. Furthermore, the ligand-binding characteristics obtained in the present study are helpful for both experimental and computational studies of CYPs and may allow future researchers to achieve desirable changes in enzymatic activities.

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“…46 However, this method can give a good rank of binding free energy for different systems, which has good correlation with experimental results. 47,48 Based on the results of MM-GB/SA (Table S1), the ΔG bind values of PT2399/0X3 in 3 models are similar, and we can find that no matter which model PT2399 may be in, its binding affinity is better than that of 0X3. This trend is consistent with the trend measured in experiments.…”

Section: The Different Binding Modes Of Pt2399 and 0x3mentioning

confidence: 91%

Exploring the inhibition mechanism on HIF‐2 by inhibitor PT2399 and 0X3 using molecular dynamics simulations

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Wang

Zheng

et al. 2018

J of Molecular Recognition

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Targeting transcription factors HIF-2 is currently considered to be the most direct way for the therapy of clear cell renal cell carcinoma. The preclinical inhibitor PT2399 and artificial inhibitor 0X3 have been identified as promising on-target inhibitors to inhibit the heterodimerization of HIF-2. However, the inhibition mechanism of PT2399 and 0X3 on HIF-2 remains unclear. To this end, molecular dynamics (MD) simulations and molecular docking were applied to investigate the effects of 2 inhibitors on structural motifs and heterodimerization of HIF-2. Our simulation results reveal that the binding of inhibitors disrupts the crucial hydrogen bond and hydrophobic interactions of interdomain of HIF-2 heterodimer due to the local conformational changes of binding interface, confirming the hypothesis that the perturbation of few residues is sufficient to disrupt the heterodimerization of HIF-2. In addition, it can be found that PT2399 with dominant substituents (cyano, fluorine, sulfuryl, and hydroxyl) is more preferred than 0X3 as HIF-2 inhibitor and these substituents play a crucial role in involving more hydrogen bond interactions with residues of interface and then cause the larger structural change of protein. This study may provide a deeper atomic-level insight into the effect of on-target inhibitors on HIF-2 heterodimer, which is expected to contribute to further rational design of effective clear cell renal cell carcinoma drugs.

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Exploring the Molecular Basis of dsRNA Recognition by Mss116p Using Molecular Dynamics Simulations and Free-Energy Calculations

Cited by 21 publications

References 50 publications

Exploring the mechanism how Marburg virus VP35 recognizes and binds dsRNA by molecular dynamics simulations and free energy calculations

Exploring the mechanism how Marburg virus VP35 recognizes and binds dsRNA by molecular dynamics simulations and free energy calculations

Molecular basis of the recognition of arachidonic acid by cytochrome P450 2E1 along major access tunnel

Exploring the inhibition mechanism on HIF‐2 by inhibitor PT2399 and 0X3 using molecular dynamics simulations

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