scholarly journals Fast Calculation of Protein–Protein Binding Free Energies Using Umbrella Sampling with a Coarse-Grained Model

2018 ◽  
Vol 14 (2) ◽  
pp. 991-997 ◽  
Author(s):  
Jagdish Suresh Patel ◽  
F. Marty Ytreberg
Keyword(s):  
Protein Binding ◽  
Umbrella Sampling ◽  
Coarse Grained ◽  
Free Energies ◽  
Fast Calculation ◽  
Coarse Grained Model ◽  
Binding Free Energies

scholarly journals Interactions Between Nucleosomes: From Atomistic Simulation to Polymer Model

2021 ◽  
Vol 8 ◽  
Author(s):  
Chengwei Zhang ◽  
Jing Huang
Keyword(s):  
Atomistic Simulation ◽  
Umbrella Sampling ◽  
Coarse Grained ◽  
Basic Unit ◽  
Time Dimension ◽  
Effective Interactions ◽  
Coarse Grained Model ◽  
Explicit Solvent ◽  
Chromatin Folding ◽  
Free Energy Landscapes

The organization of genomes in space and time dimension plays an important role in gene expression and regulation. Chromatin folding occurs in a dynamic, structured way that is subject to biophysical rules and biological processes. Nucleosomes are the basic unit of chromatin in living cells, and here we report on the effective interactions between two nucleosomes in physiological conditions using explicit-solvent all-atom simulations. Free energy landscapes derived from umbrella sampling simulations agree well with recent experimental and simulation results. Our simulations reveal the atomistic details of the interactions between nucleosomes in solution and can be used for constructing the coarse-grained model for chromatin in a bottom-up manner.

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 Protein-protein interaction-Gaussian accelerated molecular dynamics (PPI-GaMD): Characterization of protein binding thermodynamics and kinetics

2021 ◽  
Author(s):  
Jinan Wang ◽  
Yinglong Miao
Keyword(s):  
Molecular Dynamics ◽  
Potential Energy ◽  
Protein Binding ◽  
Binding Free Energy ◽  
Model System ◽  
Free Energies ◽  
Binding Thermodynamics ◽  
Accelerated Molecular Dynamics ◽  
Thermodynamics And Kinetics ◽  
Binding Free Energies

Protein-protein interactions (PPIs) play key roles in many fundamental biological processes such as cellular signaling and immune responses. However, it has proven challenging to simulate repetitive protein association and dissociation in order to calculate binding free energies and kinetics of PPIs, due to long biological timescales and complex protein dynamics. To address this challenge, we have developed a new computational approach to all-atom simulations of PPIs based on a robust Gaussian accelerated molecular dynamics (GaMD) technique. The method, termed "PPI-GaMD", selectively boosts interaction potential energy between protein partners to facilitate their slow dissociation. Meanwhile, another boost potential is applied to the remaining potential energy of the entire system to effectively model the protein's flexibility and rebinding. PPI-GaMD has been demonstrated on a model system of the ribonuclease barnase interactions with its inhibitor barstar. Six independent 2 µs PPI-GaMD simulations have captured repetitive barstar dissociation and rebinding events, which enable calculations of the protein binding thermodynamics and kinetics simultaneously. The calculated binding free energies and kinetic rate constants agree well with the experimental data. Furthermore, PPI-GaMD simulations have provided mechanistic insights into barstar binding to barnase, which involve long-range electrostatic interactions and multiple binding pathways, being consistent with previous experimental and computational findings of this model system. In summary, PPI-GaMD provides a highly efficient and easy-to-use approach for binding free energy and kinetics calculations of PPIs.

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