Trypsin-Ligand binding affinities calculated using an effective interaction entropy method under polarized force field

Cong, Yalong; Li, Mengxin; Feng, Guoqiang; Li, Yuchen; Wang, Xianwei; Duan, Lili

doi:10.1038/s41598-017-17868-z

Cited by 17 publications

(13 citation statements)

References 50 publications

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“…Some hydrogen bonds were broken or underwent large fluctuations during simulations in AMBER, while the same hydrogen bonds were well preserved during simulations in PPC. This phenomenon was also observed in many previous studies 50,82–85 . The current study highlights the important effects of electrostatic polarization on MD simulation.…”

Section: Resultssupporting

confidence: 89%

The impact of interior dielectric constant and entropic change on HIV-1 complex binding free energy prediction

Cong

Feng

et al. 2018

Structural Dynamics

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At present, the calculated binding free energy obtained using the molecular mechanics/Poisson-Boltzmann (Generalized-Born) surface area (MM/PB(GB)SA) method is overestimated due to the lack of knowledge of suitable interior dielectric constants in the simulation on the interaction of Human Immunodeficiency Virus (HIV-1) protease systems with inhibitors. Therefore, the impact of different values of the interior dielectric constant and the entropic contribution when using the MM/PB(GB)SA method to calculate the binding free energy was systemically evaluated. Our results show that the use of higher interior dielectric constants (1.4–2.0) can clearly improve the predictive accuracy of the MM/PBSA and MM/GBSA methods, and computational errors are significantly reduced by including the effects of electronic polarization and using a new highly efficient interaction entropy (IE) method to calculate the entropic contribution. The suitable range for the interior dielectric constant is 1.4–1.6 for the MM/PBSA method; within this range, the correlation coefficient fluctuates around 0.84, and the mean absolute error fluctuates around 2 kcal/mol. Similarly, an interior dielectric constant of 1.8–2.0 produces a correlation coefficient of approximately 0.76 when using the MM/GBSA method. In addition, the entropic contribution of each individual residue was further calculated using the IE method to predict hot-spot residues, and the detailed binding mechanisms underlying the interactions of the HIV-1 protease, its inhibitors, and bridging water molecules were investigated. In this study, the use of a higher interior dielectric constant and the IE method can improve the calculation accuracy of the HIV-1 system.

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Section: Resultssupporting

confidence: 89%

The impact of interior dielectric constant and entropic change on HIV-1 complex binding free energy prediction

Cong

Feng

et al. 2018

Structural Dynamics

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“…The relevant ensemble averages can be calculated by averaging over MD trajectory: The averaging procedure can be further formulated as The authors claim that the method is essentially superior to the NM approach demonstrating it to be computationally efficient and numerically reliable . Since the method was described in 2016, it has been widely applied and cited in the literature as original papers − and reviews. , …”

Section: Introductionmentioning

confidence: 99%

Protein–Ligand Interaction Energy-Based Entropy Calculations: Fundamental Challenges For Flexible Systems

et al. 2018

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Entropy calculations represent one of the most challenging steps in obtaining the binding free energy in biomolecular systems. A novel computationally effective approach (IE) was recently proposed to calculate the entropy based on the computation of protein-ligand interaction energy directly from molecular dynamics (MD) simulations. We present a study focused on the application of this method to flexible molecular systems and compare its performance with well-established normal mode (NM) and quasiharmonic (QH) entropy calculation approaches. Our results demonstrated that the IE method is intended for calculating entropy change for binding partners in fixed conformations, as by the original definition of IE, and is not applicable to the molecular complexes in which the interacting partners undergo significant conformational changes during the binding process.

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“…It is important to note that in MM/GBSA calculation, the entropy contribution can be obtained by the normal mode approach (Nguyen and Case, 1985;Brooks et al, 1995) which is often neglected because of its high computational cost and rough accuracy . On this regard, a recent method called interaction entropy (IE) (Duan et al, 2016) for calculating entropy contribution has been developed and successfully used in protein-ligand and protein-protein systems (Cong et al, 2017;Yan et al, 2017;Liu et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of Selective Binding of NMS-P118 to PARP-1 and PARP-2: A Computational Perspective

Wang

Cong

et al. 2020

Front. Mol. Biosci.

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The nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors have been proven effective to potentiate both chemotherapeutic agents and radiotherapy. However, a major problem of most current PARP inhibitors is their lack of selectivity for PARP-1 and its closest isoform PARP-2. NMS-P118 is a highly selective PARP inhibitor that binds PARP-1 stronger than PARP-2 and has many advantages such as excellent pharmacokinetic profiles. In this study, molecular dynamics (MD) simulations of NMS-P118 in complex with PARP-1 and PARP-2 were performed to understand the molecular mechanism of its selectivity. Alanine scanning together with free energy calculation using MM/GBSA and interaction entropy reveal key residues that are responsible for the selectivity. Although the conformation of the binding pockets and NMS-P118 are very similar in PARP-1 and PARP-2, most of the hot-spot residues in PARP-1 have stronger binding free energy than the corresponding residues in PARP-2. Detailed analysis of the binding energy shows that the 4 ′ 4-difluorocyclohexyl ring on NMS-P118 form favorable hydrophobic interaction with Y889 in PARP-1. In addition, the H862 residue in PARP-1 has stronger binding free energy than H428 in PARP-2, which is due to shorter distance and stronger hydrogen bonds. Moreover, the negatively charged E763 residue in PARP-1 forms stronger electrostatic interaction energy with the positively charged NMS-P118 than the Q332 residue in PARP-2. These results rationalize the selectivity of NMS-P118 and may be useful for designing novel selective PARP inhibitors.

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Trypsin-Ligand binding affinities calculated using an effective interaction entropy method under polarized force field

Cited by 17 publications

References 50 publications

The impact of interior dielectric constant and entropic change on HIV-1 complex binding free energy prediction

The impact of interior dielectric constant and entropic change on HIV-1 complex binding free energy prediction

Protein–Ligand Interaction Energy-Based Entropy Calculations: Fundamental Challenges For Flexible Systems

Molecular Mechanism of Selective Binding of NMS-P118 to PARP-1 and PARP-2: A Computational Perspective

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