Principal Component Analysis and Related Methods for Investigating the Dynamics of Biological Macromolecules

Kitao, Akio

doi:10.3390/j5020021

Cited by 38 publications

(28 citation statements)

References 131 publications

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“…In order to further understand the structural dynamics of the WT and E50A mutant picALuc, we utilized the dimensionality reduction analysis and performed principal component analysis (PCA) of their trajectories, which is known to reveal collective motions in proteins 45 using the PCA module available in the Python-based MDAnalysis package 46, 47 . Cumulative variance analysis of the principal components revealed the presence dominant collective motions in both the WT and the E50A mutant picALuc (Supplementary Figure 10) since principal components 1 and 2 (PC1 and PC2) could account for 69.8 and 19.2% of the variance in the WT protein while they could account for 74.2 and 19.8% of the variance in the E50A mutant protein.…”

Section: Resultsmentioning

confidence: 99%

A Brighter picALuc Generated Through the Loss of a Salt Bridge Interaction

Biswas

2023

Preprint

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Recently, a miniaturized variant of an artificial luciferase (ALuc), named picALuc, with a molecular weight of 13 kDa and thus, the smallest luciferase, was reported. While picALuc was found to be as active as the ALuc, questions remained on the structural organization and residue-residue interactions in the protein. Here, combining structural modeling, molecular dynamics (MD) simulations and mutational analysis, we show that the loss of a salt bridge interaction formed by Glu50 (E50) residue results in an increased enzymatic activity of picALuc. Specifically, we generated a model of picALuc using the available structure of the Gaussia luciferase (GLuc) and performed a 1 μs long Gaussian accelerated molecular dynamics (GaMD) simulation which revealed a general compaction of the protein structure as well as residue level interactions in the protein. Given that picALuc contains a number of charged residues, we focused our attention to salt bridge interactions and decided to mutate E10, E50 and D94 that were found to form a fluctuating, stable or a new salt bridge interaction, respectively. Live cell assays showed an enhanced bioluminescence in cells expressing the E50A mutant picALuc while in vitro assays revealed an increased Vmax of the E50A mutant without affecting its thermal stability. Dynamic cross-correlation and principal component analyses of the GaMD simulation trajectories revealed altered collective dynamics in the protein, in which residue E50 contributed substantially. Finally, we developed a protein fragment complementation assay using picALuc that allows monitoring protein-protein interaction in live cells. We envisage that the brighter variant of picALuc and the protein fragment complementation assay reported here will find a general applicability in developing bioluminescence-based assays and the strategy developed here will pave the way for further engineering of brighter variants of picALuc.

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Section: Resultsmentioning

confidence: 99%

A Brighter picALuc Generated Through the Loss of a Salt Bridge Interaction

Biswas

2023

Preprint

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“…This reduction in the data is derived by the linear transformation of the original variables to a set of new concerted variables, which allows one to interpret the features of the data set from only few "principal components". 27 The eigenvalues of the first 10 principal components (eigenvectors) for the ligand−ChAT complexes are shown in (Figure 11 and Figure S10). These analyses showed that the first four components explained most of the variations in the data.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…PCA allows identifying the principal components that together explain the overall motions of the protein. This reduction in the data is derived by the linear transformation of the original variables to a set of new concerted variables, which allows one to interpret the features of the data set from only few “principal components” . The eigenvalues of the first 10 principal components (eigenvectors) for the ligand–ChAT complexes are shown in (Figure and Figure S10).…”

Section: Resultsmentioning

confidence: 99%

Mechanistic Insight into the Inhibition of Choline Acetyltransferase by Proton Pump Inhibitors

Baidya

Das

Devi

et al. 2023

ACS Chem. Neurosci.

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Various pharmacoepidemiological investigational studies have indicated that Proton Pump Inhibitors (PPIs) may increase the likelihood of developing Alzheimer’s disease (AD) and non-AD related dementias. Previously, we have reported the inhibition of the acetylcholine biosynthesizing enzyme choline acetyltransferase (ChAT) by PPIs, for which omeprazole, lansoprazole, and pantoprazole exhibited IC50 values of 0.1, 1.5, and 5.3 μM, respectively. In this study we utilize a battery of computational tools to perceive a mechanistic insight into the molecular interaction of PPIs with the ChAT binding pocket that may further help in designing novel ChAT ligands. Various in-silico tools make it possible for us to elucidate the binding interaction, conformational stability, and dynamics of the protein–ligand complexes within a 200 ns time frame. Further, the binding free energies for the PPI–ChAT complexes were explored. The results suggest that the PPIs exhibit equal or higher binding affinity toward the ChAT catalytic tunnel and are stable throughout the simulated time and that the pyridine ring of the PPIs interacts primarily with the catalytic residue His324. A free energy landscape analysis showed that the folding process was linear, and the residue interaction network analysis can provide insight into the roles of various amino acid residues in stabilization of the PPIs in the ChAT binding pocket. As a major factor for the onset of Alzheimer’s disease is linked to cholinergic dysfunction, our previous and the present findings give clear insight into the PPI interaction with ChAT. The scaffold can be further simplified to develop novel ChAT ligands, which can also be used as ChAT tracer probes for the diagnosis of cholinergic dysfunction and to initiate timely therapeutic interventions to prevent or delay the progression of AD.

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“…Other methods open to researchers for analysis of energy include principal component analysis (PC), direct vector analysis and correlations such as Pearson correlation coefficient or Pearson’s R values [ 81 , 82 ]. This latter is used for analysis of energies and motions, although any two components can be tested to see if they are correlated to each other.…”

Section: Analysis Of Membrane Molecular Dynamic Simulationsmentioning

confidence: 99%

Current Trends and Changes in Use of Membrane Molecular Dynamics Simulations within Academia and the Pharmaceutical Industry

Watkins

2023

Membranes

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There has been an almost exponential increase in the use of molecular dynamics simulations in basic research and industry over the last 5 years, with almost a doubling in the number of publications each year. Many of these are focused on neurological membranes, and biological membranes in general, applied to the medical industry. A smaller portion have utilized membrane simulations to answer more basic questions related to the function of specific proteins, chemicals or biological processes. This review covers some newer studies, alongside studies from the last two decades, to determine changes in the field. Some of these are basic, while others are more profound, such as multi-component embedded membrane machinery. It is clear that many facets of the discipline remain the same, while the focus on and uses of the technology are broadening in scope and utilization as a general research tool. Analysis of recent literature provides an overview of the current methodologies, covers some of the recent trends or advances and tries to make predictions of the overall path membrane molecular dynamics will follow in the coming years. In general, the overview presented is geared towards the general scientific community, who may wish to introduce the use of these methodologies in light of these changes, making molecular dynamic simulations more feasible for general scientific or medical research.

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Principal Component Analysis and Related Methods for Investigating the Dynamics of Biological Macromolecules

Cited by 38 publications

References 131 publications

A Brighter picALuc Generated Through the Loss of a Salt Bridge Interaction

A Brighter picALuc Generated Through the Loss of a Salt Bridge Interaction

Mechanistic Insight into the Inhibition of Choline Acetyltransferase by Proton Pump Inhibitors

Current Trends and Changes in Use of Membrane Molecular Dynamics Simulations within Academia and the Pharmaceutical Industry

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