Correction to Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside-Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with Experiment

Brown, Reid F.; Andrews, Casey T.; Elcock, Adrian H.

doi:10.1021/acs.jctc.8b00594

Cited by 2 publications

(3 citation statements)

References 4 publications

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“…However, the NTP-based coacervates exhibited significantly different critical salt concentrations at the same temperature (and different UCST at the same salt concentration). The critical salt concentration decreased in the order GTP/PLys (G) > ATP/PLys (A) > CTP/PLys (C) ≥ UTP/PLys (U) > TTP/PLys (T), in line with the relative stacking free energies of the nucleobases . In addition, the critical salt concentration increased more rapidly with decreasing temperature for ATP and GTP than for CTP, TTP, and UTP.…”

Section: Resultsmentioning

confidence: 83%

“…The critical salt concentration decreased in the order GTP/PLys (G) > ATP/PLys (A) > CTP/PLys (C) ≥ UTP/PLys (U) > TTP/PLys (T), in line with the relative stacking free energies of the nucleobases. 41 In addition, the critical salt concentration increased more rapidly with decreasing temperature for ATP and GTP than for CTP, TTP, and UTP.…”

Section: ■ Results and Discussionmentioning

confidence: 98%

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Temperature-Responsive Peptide–Nucleotide Coacervates

Lu¹,

Nakashima²,

Spruijt³

2021

J. Phys. Chem. B

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Coacervates are a type of liquid–liquid phase separated (LLPS) droplets that can serve as models of membraneless organelles (MLOs) in living cells. Peptide–nucleotide coacervates have been widely used to mimic properties of ribonucleoprotein (RNP) granules, but the thermal stability and the role of base stacking is still poorly understood. Here, we report a systematic investigation of coacervates formed by five different nucleoside triphosphates (NTPs) with poly- l -lysine and poly- l -arginine as a function of temperature. All studied combinations exhibit an upper critical solution temperature (UCST), and a temperature-dependent critical salt concentration, originating from a significant nonelectrostatic contribution to the mixing free energy. Both the enthalpic and entropic parts of this nonelectrostatic interaction decrease in the order G/A/U/C/T, in accordance with nucleobase stacking free energies. Partitioning of two dyes proves that the local hydrophobicity inside the peptide–nucleotide coacervates is different for every nucleoside triphosphate. We derive a simple relation between the temperature and salt concentration at the critical point based on a mean-field model of phase separation. Finally, when different NTPs are mixed with one common oppositely charged peptide, hybrid coacervates were formed, characterized by a single intermediate UCST and critical salt concentration. NTPs with lower critical salt concentrations can remain condensed in mixed coacervates far beyond their original critical salt concentration. Our results show that NTP-based coacervates have a strong temperature sensitivity due to base stacking interactions and that mixing NTPs can significantly influence the stability of condensates and, by extension, their bioavailability.

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Section: Resultsmentioning

confidence: 83%

Section: ■ Results and Discussionmentioning

confidence: 98%

Temperature-Responsive Peptide–Nucleotide Coacervates

Lu¹,

Nakashima²,

Spruijt³

2021

J. Phys. Chem. B

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“…For example, commonly used force elds and water models tend to overstabilize proteins and underestimate their radii of gyration in the unfolded state 43,44 ; the ff14SB 45 and ff19SB protein force elds overestimate amino acid helical propensities with the TIP3P water model 46 ; force elds also tend to overestimate the secondary structure content in simulations of intrinsically disordered proteins 47 ; the osmotic pressure of guanidinium -acetate analog mixtures computed with CHARMM36 48 is signi cantly lower than the experimental value 49 , indicating that the force eld overestimates guanidinium -acetate interactions; overestimated cation -phosphate interactions overcondense DNA in simulations 50,51 ; CHARMM27r underestimates the area per lipid, suggesting that the head groups attract one another too strongly 52 ; authors have noted erroneous clustering of ions in simulations performed using standard force elds 53,54 ; TIP3P grossly overestimates the self diffusion and isothermal compressibility of water, among other de ciencies, which OPC was developed to address 34 . It has also been pointed out that carbohydrates are too selfattracting in CHARMM, AMBER, and OPLS 55,56 , which in addition have awed DNA base-stacking and ion -phosphate parameters which fail to reproduce the correct population ensembles in silico 57 . This is by no means an exhaustive list of known force eld de ciencies, many of which have been reviewed in more depth by Yoo and Aksimentiev who also suggest elegant modi cations to the standard force elds to ameliorate some of these shortcomings 58 .…”

Section: Discussionmentioning

confidence: 99%

Calculated hydration free energies become less accurate with increases in molecular weight

Ivanov

2024

Preprint

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In order for computer-aided drug design to fulfil its long held promise of delivering new medicines faster and cheaper, extensive development and validation work must be done first. This pertains particularly to molecular dynamics force fields where one important aspect – the hydration free energy (HFE) of small molecules – is often insufficiently and deceptively analyzed and reported. While most benchmarking studies report excellent accuracies of calculated hydration free energies – usually within 2 kcal/mol of the experimental values – we find that deeper analysis reveals significant shortcomings. Herein, we report a dependence of HFE prediction errors on ligand molecular weight – the higher the weight, the bigger the prediction error and the higher the probability the calculated result is erroneous by a large residual. We show that in the drug-like molecular weight region, HFE predictions can easily be off by 5 kcal/mol or more. This is likely to be highly problematic in a drug discovery and development setting. These findings should be taken into consideration during development and testing of the next generation of force fields, if they are to usher in the next generation of antineoplastics.

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Correction to Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside-Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with Experiment

Cited by 2 publications

References 4 publications

Temperature-Responsive Peptide–Nucleotide Coacervates

Temperature-Responsive Peptide–Nucleotide Coacervates

Calculated hydration free energies become less accurate with increases in molecular weight

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