Lessons learned about steered molecular dynamics simulations and free energy calculations

Boubeta, Fernando Martín; García, Rocío María Contestín; Lorenzo, Ezequiel Norberto; Boechi, Leonardo; Estrin, Darı́o A.; Sued, Mariela; Arrar, Mehrnoosh

doi:10.1111/cbdd.13485

Cited by 23 publications

(17 citation statements)

References 49 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It remains an interesting and open question whether peak forces for scaffold dislocation could be used to predict the yield of experimentally synthesized nanodiscs or whether differences in peak forces measured for different lipid loading could translate into differences in yield for syntheses having different lipid:scaffold stoichiometries or even a distribution of nanodiscs having different APL within a single experiment. If yields or distributions of nanodiscs having different lipid loading could be accurately measured, then it is possible that the combination of SMD with the Jarzinski equality could quantitatively predict these yields or distributions. − …”

Section: Resultsmentioning

confidence: 99%

Properties of DNA- and Protein-Scaffolded Lipid Nanodiscs

Maingi

Rothemund

2020

ACS Nano

View full text Add to dashboard Cite

The properties of natural lipid bilayers are vital to the regulation of many membrane proteins. Scaffolded nanodiscs provide an in vitro lipid bilayer platform to host membrane proteins in an environment that approximates native lipid bilayers. However, the properties of scaffold-enclosed bilayers may depart significantly from those of bulk cellular membranes. Therefore, to improve the usefulness of nanodiscs it is essential to understand the properties of lipids restricted by scaffolds. We used computational molecular dynamics and modeling approaches to understand the effects of nanodisc size, scaffold type (DNA or protein), and hydrophobic modification of DNA scaffolds on bilayer stability and degree to which the properties of enclosed bilayers approximate bulk bilayers. With respect to achieving bulk bilayer behavior, we found that charge neutralization of DNA scaffolds was more important than the total hydrophobic content of their modifications: bilayer properties were better for scaffolds having a large number of short alkyl chains than those having fewer long alkyl chains. Further, complete charge neutralization of DNA scaffolds enabled better lipid binding, and more stable bilayers, as shown by steered molecular dynamics simulations that measured the force required to dislodge scaffolds from lipid bilayer patches. Considered together, our simulations provide a guide to the design of DNA-scaffolded nanodiscs suitable for studying membrane proteins.

show abstract

Section: Resultsmentioning

confidence: 99%

Properties of DNA- and Protein-Scaffolded Lipid Nanodiscs

Maingi

Rothemund

2020

ACS Nano

View full text Add to dashboard Cite

show abstract

“…Specifically, this unbinding event is roughly captured by adding an extra harmonic bias potential along the reaction coordinate to the Hamiltonian. Subsequently, the protein is pulled away from the RNA with a constant velocity. , …”

Section: Methodsmentioning

confidence: 99%

“…Subsequently, the protein is pulled away from the RNA with a constant velocity. 49,50 The cv-SMD simulations were performed using the GROMACS 2018.3 38 package to initiate the umbrella sampling free energy calculations. The distance between the center of mass of the TAR RNA and the center of mass of the Tat peptide was chosen as the reaction coordinate for pulling the Tat peptide out of its binding site in the TAR RNA.…”

Section: ■ Introductionmentioning

confidence: 99%

Correlation in Domain Fluctuations Navigates Target Search of a Viral Peptide along RNA

et al. 2021

View full text Add to dashboard Cite

Biological macromolecules often exhibit correlations in fluctuations involving distinct domains. This study decodes their functional implications in RNA–protein recognition and target-specific binding. The target search of a peptide along RNA in a viral TAR–Tat complex is closely monitored using atomistic simulations, steered molecular dynamics simulations, free energy calculations, and a machine-learning-based clustering technique. An anticorrelated domain fluctuation is identified between the tetraloop and the bulge region in the apo form of TAR RNA that sets a hierarchy in the domain-specific fluctuations at each binding event and that directs the succeeding binding footsteps. Thus, at each binding footstep, the dynamic partner selects an RNA location for binding where it senses a higher fluctuation, which is conventionally reduced upon binding. This event stimulates an alternate domain fluctuation, which then dictates sequential binding footstep/s and thus the search progresses. Our cross-correlation maps show that the fluctuations relay from one domain to another specific domain until the anticorrelation between those interdomain fluctuations sustains. Artificial attenuation of that hierarchical domain fluctuation inhibits specific RNA binding. The binding is completed with the arrival of a few long-lived water molecules that mediate slightly distant RNA–protein sites and finally stabilize the overall complex. The study underscores the functional importance of naturally designed fluctuating RNA motifs (bulge, tetraloop) and their interplay in dictating the directionality of the search in a highly dynamic environment.

show abstract

“…5.7. Steered molecular dynamics (SMD) simulations SMD allows to analyze the amount of external force required to unbind ligand from its binding site in protein 51 . One of the most used GROMACS package was employed to perform SMD simulations.…”

Section: Molecular Dynamics (Md) Simulations and Thermodynamic Free E...mentioning

confidence: 99%

Theaflavin 3-gallate inhibits the main protease (Mpro) of SARS-CoV-2 and reduces its count in vitro

Chauhan

Bhardwaj

Kumar

et al. 2022

Preprint

View full text Add to dashboard Cite

Main protease (Mpro) of SARS-CoV-2 is crucial for its replication/infection and has been recognized as an attractive drug target. In this study, we identified theaflavin 3-gallate as an inhibitor of Mpro protein of SARS-CoV-2 with IC50 value of 18.48 ± 1.29 µM. Compared to theaflavin, theaflavin 3-gallate exhibited superior antiviral activity and at a concentration of 200 µM reduced the viral count by 75% (viral particles reduced from 106.7 to 106.1). Time-dependent analyses of conventional and steered MD-simulations revealed stronger interactions of theaflavin 3-gallate with the active site residues of Mpro than the standard molecule GC373 and theaflavin. Taken together, our findings suggest that theaflavin 3-gallate can be developed into a potential lead molecule against SARS-CoV-2.

show abstract

Lessons learned about steered molecular dynamics simulations and free energy calculations

Cited by 23 publications

References 49 publications

Properties of DNA- and Protein-Scaffolded Lipid Nanodiscs

Properties of DNA- and Protein-Scaffolded Lipid Nanodiscs

Correlation in Domain Fluctuations Navigates Target Search of a Viral Peptide along RNA

Theaflavin 3-gallate inhibits the main protease (Mpro) of SARS-CoV-2 and reduces its count in vitro

Contact Info

Product

Resources

About