GRadient Adaptive Decomposition (GRAD) Method: Optimized Refinement Along Macrostate Borders in Markov State Models

Romano, Pablo; Guenza, Marina

doi:10.1021/acs.jcim.7b00261

Cited by 3 publications

(2 citation statements)

References 47 publications

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“…For PCA and t-SNE, the optimal parameter of the number of dimensions is in the tens. Two dimensions are typically used for MSM construction and visualization purpose. − In this regard, supervised ivis exhibited the highest GMRQ value.…”

Section: Resultsmentioning

confidence: 99%

ivis Dimensionality Reduction Framework for Biomacromolecular Simulations

Tian

Tao

2020

J. Chem. Inf. Model.

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Molecular dynamics (MD) simulations have been widely applied to study macro-molecules including proteins. However, high-dimensionality of the datasets produced by simulations makes it difficult for thorough analysis, and further hinders a deeper understanding of biomacromolecules. To gain more insights into the protein structure-function relations, appropriate dimensionality reduction methods are needed to project simulations onto low-dimensional spaces. Linear dimensionality reduction methods, such as principal component analysis (PCA) and time-structure based independent component analysis (t-ICA), could not preserve sufficient structural information. Though better than linear methods, nonlinear methods, such as t-distributed stochastic neighbor embedding (t-SNE), still suffer from the limitations in avoiding system noise and keeping inter-cluster relations. ivis is a novel deep learning-based dimensionality reduction method originally developed for single-cell datasets. Here we applied this framework for the study of light, oxygen and voltage (LOV) domain of diatom Phaeodactylum tricornutum aureochrome 1a (PtAu1a). Compared with other methods, ivis is shown to be superior in constructing Markov state model (MSM), preserving information of both local and global distances and maintaining similarity between high dimension and low dimension with the least information loss. Moreover, ivis framework is capable of providing new prospective for deciphering residue-level protein allostery through the feature weights in the neural network. Overall, ivis is a promising member in the analysis toolbox for proteins.

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Section: Resultsmentioning

confidence: 99%

ivis Dimensionality Reduction Framework for Biomacromolecular Simulations

Tian

Tao

2020

J. Chem. Inf. Model.

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“…Thus, the high energy regions in the free energy map may display roughness, which can be smoothed to avoid overfitting. 48,49 However this step is not needed in our study because the results of our analysis depend largely on the minima of the free energy maps, which are statistically well sampled.…”

Section: H Po H Pomentioning

confidence: 99%

Dinucleotides as simple models of the base stacking-unstacking component of DNA ‘breathing’ mechanisms

Beyerle

Dinpajooh

et al. 2020

Preprint

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Regulatory protein access to the DNA duplex 'interior' depends on local DNA 'breathing' fluctuations, and the most fundamental of these are thermally-driven base stacking-unstacking interactions. The smallest DNA unit that can undergo such transitions is the dinucleotide, whose structural and dynamic properties are dominated by stacking, while the ion condensation, cooperative stacking and inter-base hydrogen-bonding, present in duplex DNA are not involved. We use dApdA to study stacking-unstacking at the dinucleotide level because the fluctuations observed are likely to resemble those of larger DNA molecules, but in the absence of constraints introduced by cooperativity are likely to be more pronounced, and thus more accessible to measurement. We study these fluctuations with a combination of Molecular Dynamics simulations on the microsecond timescale and Markov State Model analyses, and validate our results by calculations of circular dichroism (CD) spectra, with results that agree well with experiments. Our analyses show that the CD spectrum of dApdA is defined by two distinct chiral conformations that correspond, respectively, to a Watson-Crick form and a hybrid form with one base in a Hoogsteen configuration. We find also that ionic structure and water orientation around dApdA play important roles in controlling its breathing fluctuations.

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Dinucleotides as simple models of the base stacking-unstacking component of DNA ‘breathing’ mechanisms

Beyerle

Dinpajooh

et al. 2021

Nucleic Acids Research

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Regulatory protein access to the DNA duplex ‘interior’ depends on local DNA ‘breathing’ fluctuations, and the most fundamental of these are thermally-driven base stacking-unstacking interactions. The smallest DNA unit that can undergo such transitions is the dinucleotide, whose structural and dynamic properties are dominated by stacking, while the ion condensation, cooperative stacking and inter-base hydrogen-bonding present in duplex DNA are not involved. We use dApdA to study stacking-unstacking at the dinucleotide level because the fluctuations observed are likely to resemble those of larger DNA molecules, but in the absence of constraints introduced by cooperativity are likely to be more pronounced, and thus more accessible to measurement. We study these fluctuations with a combination of Molecular Dynamics simulations on the microsecond timescale and Markov State Model analyses, and validate our results by calculations of circular dichroism (CD) spectra, with results that agree well with the experimental spectra. Our analyses show that the CD spectrum of dApdA is defined by two distinct chiral conformations that correspond, respectively, to a Watson–Crick form and a hybrid form with one base in a Hoogsteen configuration. We find also that ionic structure and water orientation around dApdA play important roles in controlling its breathing fluctuations.

show abstract

GRadient Adaptive Decomposition (GRAD) Method: Optimized Refinement Along Macrostate Borders in Markov State Models

Cited by 3 publications

References 47 publications

ivis Dimensionality Reduction Framework for Biomacromolecular Simulations

ivis Dimensionality Reduction Framework for Biomacromolecular Simulations

Dinucleotides as simple models of the base stacking-unstacking component of DNA ‘breathing’ mechanisms

Dinucleotides as simple models of the base stacking-unstacking component of DNA ‘breathing’ mechanisms

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