The Conveyor Belt Umbrella Sampling (CBUS) Scheme: Principle and Application to the Calculation of the Absolute Binding Free Energies of Alkali Cations to Crown Ethers

2020 ◽  
Vol 16 (4) ◽  
pp. 2474-2493 ◽  
Author(s):  
David F. Hahn ◽  
Rhiannon A. Zarotiadis ◽  
Philippe H. Hünenberger
Keyword(s):  
Crown Ethers ◽  
Conveyor Belt ◽  
Umbrella Sampling ◽  
Free Energies ◽  
Alkali Cations ◽  
The Absolute ◽  
Binding Free Energies

scholarly journals A replica exchange umbrella sampling (REUS) approach to predict host–guest binding free energies in SAMPL8 challenge

2021 ◽  
Author(s):  
Mahdi Ghorbani ◽  
Phillip S. Hudson ◽  
Michael R. Jones ◽  
Félix Aviat ◽  
Rubén Meana-Pañeda ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Umbrella Sampling ◽  
Free Energy Calculations ◽  
Replica Exchange ◽  
Free Energies ◽  
Guest Binding ◽  
Binding Free Energy Calculations ◽  
Force Field Parameters ◽  
Binding Free Energies

AbstractIn this study, we report binding free energy calculations of various drugs-of-abuse to Cucurbit-[8]-uril as part of the SAMPL8 blind challenge. Force-field parameters were obtained from force-matching with different quantum mechanical levels of theory. The Replica Exchange Umbrella Sampling (REUS) approach was used with a cylindrical restraint to enhance the sampling of host–guest binding. Binding free energy was calculated by pulling the guest molecule from one side of the symmetric and cylindrical host, then into and through the host, and out the other side (bidirectional) as compared to pulling only to the bound pose inside the cylindrical host (unidirectional). The initial results with force-matched MP2 parameter set led to RMSE of 4.68 $${\text{kcal}}/{\text{mol}}$$ kcal / mol from experimental values. However, the follow-up study with CHARMM generalized force field parameters and force-matched PM6-D3H4 parameters resulted in RMSEs from experiment of $$2.65$$ 2.65 and $$1.72 {\text{kcal}}/{\text{mol}}$$ 1.72 kcal / mol , respectively, which demonstrates the potential of REUS for accurate binding free energy calculation given a more suitable description of energetics. Moreover, we compared the free energies for the so called bidirectional and unidirectional free energy approach and found that the binding free energies were highly similar. However, one issue in the bidirectional approach is the asymmetry of profile on the two sides of the host. This is mainly due to the insufficient sampling for these larger systems and can be avoided by longer sampling simulations. Overall REUS shows great promise for binding free energy calculations.

scholarly journals Calculations of the absolute binding free energies for Ralstonia solanacearum lectins bound with methyl-α-l-fucoside at molecular mechanical and quantum mechanical/molecular mechanical levels

RSC Advances ◽  
2017 ◽  
Vol 7 (61) ◽  
pp. 38570-38580 ◽  
Author(s):  
Wei Liu ◽  
Xiangyu Jia ◽  
Meiting Wang ◽  
Pengfei Li ◽  
Xiaohui Wang ◽  
...  
Keyword(s):  
Ralstonia Solanacearum ◽  
Quantum Mechanical ◽  
Binding Affinities ◽  
Free Energies ◽  
The Absolute ◽  
Binding Free Energies

In this work, both a molecular mechanical (MM) method and a hybrid quantum mechanical/molecular mechanical (QM/MM) method have been applied in the study of the binding affinities of methyl-α-l-fucoside to Ralstonia solanacearum lectins.

scholarly journals Calculation of absolute binding free energies between the hERG channel and structurally diverse drugs

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Tatsuki Negami ◽  
Mitsugu Araki ◽  
Yasushi Okuno ◽  
Tohru Terada
Keyword(s):  
Action Potentials ◽  
Binding Free Energy ◽  
Herg Channel ◽  
Free Energies ◽  
Docking Simulations ◽  
Cryo Electron Microscopy ◽  
The Absolute ◽  
Experimental Structure ◽  
Absolute Binding Free Energy ◽  
Binding Free Energies

Abstract The human ether-a-go-go-related gene (hERG) encodes a voltage-gated potassium channel that plays an essential role in the repolarization of action potentials in cardiac muscle. However, various drugs can block the ion current by binding to the hERG channel, resulting in potentially lethal cardiac arrhythmia. Accordingly, in silico studies are necessary to clarify the mechanisms of how these drugs bind to the hERG channel. Here, we used the experimental structure of the hERG channel, determined by cryo-electron microscopy, to perform docking simulations to predict the complex structures that occur between the hERG channel and structurally diverse drugs. The absolute binding free energies for the models were calculated using the MP-CAFEE method; calculated values were well correlated with experimental ones. By applying the regression equation obtained here, the affinity of a drug for the hERG channel can be accurately predicted from the calculated value of the absolute binding free energy.

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