Molecular dynamics study of biomembrane/local anesthetics interactions

Bernardi, Rafael C.; Gomes, Diego E. B.; Gobato, Ricardo; Taft, Carlton A.; Ota, André Tsutomu; Pascutti, Pedro Geraldo

doi:10.1080/00268970902926238

Cited by 21 publications

(29 citation statements)

References 48 publications

(69 reference statements)

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“…Since a plethora of biochemical phenomena takes place within lipid membranes and their interface with water, investigating the interaction between lipids and other biomolecules is of high interest [97,98]. For instance, G-Protein Couple Receptors are one of the most targeted protein classes for drug discovery, and they exist mainly as membrane-embedded proteins [99][100][101].…”

Section: Identifying Lipid-protein Partnersmentioning

confidence: 99%

Generalized correlation-based dynamical network analysis: a new high-performance approach for identifying allosteric communications in molecular dynamics trajectories

Melo

Bernardi

Fuente-Núñez

et al. 2020

Preprint

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Molecular interactions are essential for regulation of cellular processes, from the formation of multiprotein complexes, to the allosteric activation of enzymes. Identifying the essential residues and molecular features that regulate such interactions is paramount for understanding the biochemical process in question, allowing for suppression of a reaction through drug interventions, or optimization of a chemical process using bioengineered molecules. In order to identify important residues and information pathways within molecular complexes, the Dynamical Network Analysis method was developed and has since been broadly applied in the literature. However, in the dawn of exascale computing, this method is generally limited to relatively small biomolecular systems. In this work we provide an evolution of the method, application and interface. All data processing and analysis is conducted through Jupyter notebooks, providing automatic detection of important solvent and ion residues, an optimized and parallel generalized correlation implementation that is linear with respect to the number of nodes in the system, and subsequent community clustering, calculation of betweenness of contacts, and determination optimal paths. Using the popular visualization program VMD, high-quality renderings of the networks over the biomolecular structures can be produced. Our new implementation was employed to investigate three different systems, with up to 2.5 M atoms, namely the OMP-decarboxylase, the Leucyl-tRNA synthetase complexed with its cognate tRNA and adenylate, and the respiratory complex I in a membrane environment. Our enhanced and updated protocol provides the community with an intuitive and interactive interface, which can be easily applied to large macromolecular complexes.In the last few decades molecular dynamics (MD) simulations have become an indispensable tool for mechanistic analysis in structural biology. From its first applications, revealing the fluid-like interior of protein that result from the diffusional character of local atomic motion [1], to more recent applications simulating entire organelles [2], the information content generated by MD studies has grown rapidly. With the increase of system sizes [3] and the frequent use of enhanced sampling techniques [4,5], came the 1/25 need for new and enhanced analysis tools, capable of extracting information from massive amounts of data and generating new insight. The most diverse approaches have been applied to identify system features that are relevant to its biological functions, including clustering algorithms [6,7], dimensionality reduction techniques [8], and a variety of strategies from the so-called "big-data" and "artificial intelligence" fields [9][10][11]. Developed just over a decade ago [12,13], a particularly interesting technique that has recently become popular is the analysis of dynamical networks [14][15][16]. This technique has been employed to study how groups of atoms interconnect in "communities" [17], and also the allosteric signaling in tRN...

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Section: Identifying Lipid-protein Partnersmentioning

confidence: 99%

Generalized correlation-based dynamical network analysis: a new high-performance approach for identifying allosteric communications in molecular dynamics trajectories

Melo

Bernardi

Fuente-Núñez

et al. 2020

Preprint

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“…Collective variables were analyzed using in-house python scripts implemented in Jupyter notebooks. Following previously stablished protocols (112,113), we analyzed the simulations in direct comparison it with experimental data.…”

Section: Hybrid Qm/mm String Simulationsmentioning

confidence: 99%

Bacteria on steroids: the enzymatic mechanism of an NADH-dependent dehydrogenase that regulates the conversion of cortisol to androgen in the gut microbiome

Bernardi

Doden

Melo

et al. 2020

Preprint

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The ability to metabolize both endogenous and exogenous compounds to a variety of metabolic products is not exclusive to our human cells. In fact, the bacterial communities that inhabit our digestive system are responsible for a network of steroid transformations that can produce hormones in the gut, which are then absorbed to act in the host. These communities have been shown to impact our health in numerous ways, affecting disease predisposition, pathogenesis, physical fitness, and dietary responsiveness. Steroid biotransformations by gut bacteria are predicted to impact the host endocrine system. A particular set of transformations facilitated by microbial enzymes has been shown to result in the formation of 11-oxy-androgens from hostderived cortisol. Since androgens have been implicated in disease and immune modulations, understanding the structure and catalytic mechanism of enzymes involved in cortisol metabolism is a key step to hasten the development of strategies that reduce the formation of disease-promoting bioactive steroids in certain individuals. Here, we combine experimental and computational techniques to describe DesC, an enzyme capable of creating 20a-dihydrocortisol and siphoning cortisol away from pathways that produce androgens. DesC diverges significantly from previously described bacterial and eukaryotic counterparts, catalyzing an NADH-dependent 20ahydroxysteroid dehydrogenase reaction but presenting little sequence and structure similarity to them. The structural information obtained by X-ray crystallography and hybrid QM/MM simulations, validated through mutagenesis studies, show the reaction occurs through a multi-step proton relay mechanism. Free energy calculations were then used to describe the kinetics of the reaction mechanism. The mechanistic information presented here can be employed in the development of therapeutics to divert microbial pathways away from disease-promoting steroids. AUTHOR INFORMATION Corresponding Author

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“…However, the exact dynamics of LAs remain mostly unclear 7 . Because of a lack of structural data on membrane proteins, nobody is sure whether LAs exert their effects directly on the Na+ channels or indirectly on the surrounding phospholipids 8 .…”

Section: La Mechanism: a General Overviewmentioning

confidence: 99%

The Effects of Benzene Substituents and Intermediate Linkage on Local Anesthetic Effectiveness

Bommineni

2019

Preprint

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There are many experimental studies on the effectiveness of clinically effective local anesthetics (LA). Although an atomic analysis of LAs would contribute to understanding the factors that influence their effectiveness, there have been no theoretical studies performed thus far. Previous prominent papers in the field have examined the aromatic ring and amine terminal of LAs in great detail. In this paper, I establish which type of intermediate linkage -ester or amide -lends to a relatively greater effectiveness. I also elucidate the extent to which substitutions on the LA's benzene ring differentially influence amino esters' and amino amides' relative effectiveness. Using novel structure-based drug design (SBDD) techniques, I observed that LA effectiveness is influenced more by benzene ring substitutions and, to a lesser degree, by the type of intermediate linkage.

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Molecular dynamics study of biomembrane/local anesthetics interactions

Cited by 21 publications

References 48 publications

Generalized correlation-based dynamical network analysis: a new high-performance approach for identifying allosteric communications in molecular dynamics trajectories

Generalized correlation-based dynamical network analysis: a new high-performance approach for identifying allosteric communications in molecular dynamics trajectories

Bacteria on steroids: the enzymatic mechanism of an NADH-dependent dehydrogenase that regulates the conversion of cortisol to androgen in the gut microbiome

The Effects of Benzene Substituents and Intermediate Linkage on Local Anesthetic Effectiveness

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