Automated Search of Minimum Free‐Energy Path by Umbrella Integration

Mitsuta, Yuki; Yamanaka, Shusuke; Kawakami, Takashi; Okumura, Mitsutaka

doi:10.1002/jcc.25367

Cited by 4 publications

(4 citation statements)

References 46 publications

(56 reference statements)

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“…The calculation script of the SHS method was reconstructed using the script of the FERRMap approach. 49 In addition, the L-BFGS method 50,51 was employed to find the EQ points and ADD, and the dimer method 52−55 was utilized to determine the TS points. If the dimer approach was deemed ineffective during the optimization, the Newton−Raphson method was applied instead.…”

Section: ■ Methodsmentioning

confidence: 99%

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Analytical Method Using a Scaled Hypersphere Search for High-Dimensional Metadynamics Simulations

Mitsuta

Shigeta

2020

J. Chem. Theory Comput.

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Metadynamics (MTD) is one of the most effective methods for calculating the free energy surface and finding rare events. Nevertheless, numerous studies using MTD have been carried out using 3D or lower dimensional collective variables (CVs), as higher dimensional CVs require costly computational resources and the obtained results are too complex to understand the important events. The latter issue can be conveniently solved by utilizing the free energy reaction network (FERN), which is a graph structure consisting of edges of minimum free energy paths (MFEPs), nodes of equation (EQ) points, and transition state (TS) points. In the present article, a new method for exploring FERNs on high-dimensional CVs using MTD and the scaled hypersphere search (SHS) method is described. A test calculation based on the MTD-SHS simulation of met-enkephalin in explicit water with 7 CVs was conducted. As a result, 889 EQ points and 1805 TS points were found. The MTD-SHS approach can find MFEPs exhaustively; therefore, the FERNs can be estimated without any a priori knowledge of the EQ and TS points.

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Section: ■ Methodsmentioning

confidence: 99%

“…The calculation script of the SHS method was reconstructed using the script of the FERRMap approach . In addition, the L-BFGS method , was employed to find the EQ points and ADD, and the dimer method − was utilized to determine the TS points.…”

Section: Methodsmentioning

confidence: 99%

Analytical Method Using a Scaled Hypersphere Search for High-Dimensional Metadynamics Simulations

Mitsuta

Shigeta

2020

J. Chem. Theory Comput.

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“…US [83][84][85] simulations use a series of differently positioned biasing potentials along the examined reaction coordinates to ensure proper sampling of high energy regions, in particular transitions states and their proximity. The weighted histogram analysis method (WHAM) [86] is perhaps the most widely used post-processing method to construct the PMF from the biased distribution of states, but other strategies, like umbrella integration [87] can also be applied. The key parameters for US are the force constant of the biasing potential and the distance between the middle of the potentials in neighboring windows.…”

Section: Qm/mm Approaches For Free Energy Calculationsmentioning

confidence: 99%

The role of quantum chemistry in covalent inhibitor design

Mihalovits

Ferenczy

Keserü

2021

Int J of Quantum Chemistry

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The recent ascent of targeted covalent inhibitors (TCI) in drug discovery brings new opportunities and challenges to quantum chemical reactivity calculations supporting discovery efforts. TCIs typically form a covalent bond with the targeted nucleophilic amino acid side chain. Their reactivity that can be both computed and experimentally measured is therefore one of the key factors in determining inhibitory potency. Calculation of relevant quantum chemical descriptors and corresponding reaction barriers of model reactions represent efficient ways to predict intrinsic reactivities of covalent ligands. A more comprehensive description of covalent ligand binding is offered by mixed quantum mechanical/molecular mechanical (QM/MM) potentials.Reaction mechanisms can be investigated by the exploration of the potential energy surface as a function of suitable reaction coordinates, and free energy surfaces can also be calculated with molecular dynamics based simulations. Here we review the methodological aspects and discuss applications with primary focus on high-end QM/MM simulations to illustrate the current status of quantum chemical support to covalent inhibitor design. Available QM approaches are suitable to identify likely reaction mechanisms and rate determining steps in the binding of covalent inhibitors.The efficient QM/MM prediction of ligand reactivities complemented with the computational description of the recognition step makes these computations highly useful in covalent drug discovery.

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“…Complementary to experimental approaches, molecular dynamics (MD) simulation has been frequently adopted in discovering the atomic details of the protein‐protein interactions . As computational power increases, some researchers have applied the classical MD simulation in large virus systems, though the simulations can be computationally expensive and the systems may remain trapped in local minima . Simulation convergence usually requires timescales of microseconds to milliseconds for such large protein complexes; otherwise, the sampling is often inadequate .…”

Section: Introductionmentioning

confidence: 99%

Investigating the stability of dengue virus envelope protein dimer using well‐tempered metadynamics simulations

Zhang

Kai

2019

Proteins

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We explored the stability of the dengue virus envelope (E) protein dimer since it is widely assumed that the E protein dimer is stabilized by drug ligands or antibodies in an acidic environment, neutralizing the virus's ability to fuse with human cells. During this process, a large conformational change of the E protein dimer is required. We performed Molecular Dynamics simulations to mimic the conformational change and stability of the dimer in neutral and acidic conditions with the well‐tempered metadynamics method. Furthermore, as a few neutralizing antibodies discovered from dengue patients were reported, we used the same simulation method to examine the influence of a selected antibody on the dimer stability in both neutral and acidic conditions. We also investigated the antibody's influence on a point‐mutated E protein that had been reported to interrupt the protein‐antibody interaction and result in more than 95% loss of the antibody's binding ability. Our simulation results are highly consistent with the experimental conclusion that binding of the antibody to the E protein dimer neutralizes the virus, especially in a low pH condition, while the mutation of W101A or N153A significantly reduces the antibody's ability in stabilizing the E protein dimer. We demonstrate that well‐tempered metadynamics can be used to accurately explore the antibody's interaction on large protein complexes such as the E protein dimer, and the computational approach in this work is promising in future antibody development.

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Automated Search of Minimum Free‐Energy Path by Umbrella Integration

Cited by 4 publications

References 46 publications

Analytical Method Using a Scaled Hypersphere Search for High-Dimensional Metadynamics Simulations

Analytical Method Using a Scaled Hypersphere Search for High-Dimensional Metadynamics Simulations

The role of quantum chemistry in covalent inhibitor design

Investigating the stability of dengue virus envelope protein dimer using well‐tempered metadynamics simulations

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