Extensive tests and evaluation of the CHARMM36IDPSFF force field for intrinsically disordered proteins and folded proteins

Liu, Hao; Dong, Song; Zhang, Yangpeng; Yang, Sheng; Luo, Ray; Chen, Haifeng

doi:10.1039/c9cp03434j

Cited by 41 publications

(36 citation statements)

References 68 publications

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“…Accurate conformational sampling of IDPs is a major challenge in the field of molecular simulations where conventional forcefields do not seem to accurately reproduce the properties of IDPs. Several solutions toward fixing the forcefield transferability issues have been suggested and applied extensively to IDPs 28 – 31 . What stands out in these improvements is the necessity to have a balanced protein–water interactions besides the required changes in the parameters of proteins 32 , 33 .…”

Section: Resultsmentioning

confidence: 99%

High resolution ensemble description of metamorphic and intrinsically disordered proteins using an efficient hybrid parallel tempering scheme

2021

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Mapping free energy landscapes of complex multi-funneled metamorphic proteins and weakly-funneled intrinsically disordered proteins (IDPs) remains challenging. While rare-event sampling molecular dynamics simulations can be useful, they often need to either impose restraints or reweigh the generated data to match experiments. Here, we present a parallel-tempering method that takes advantage of accelerated water dynamics and allows efficient and accurate conformational sampling across a wide variety of proteins. We demonstrate the improved sampling efficiency by benchmarking against standard model systems such as alanine di-peptide, TRP-cage and β-hairpin. The method successfully scales to large metamorphic proteins such as RFA-H and to highly disordered IDPs such as Histatin-5. Across the diverse proteins, the calculated ensemble averages match well with the NMR, SAXS and other biophysical experiments without the need to reweigh. By allowing accurate sampling across different landscapes, the method opens doors for sampling free energy landscape of complex uncharted proteins.

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Section: Resultsmentioning

confidence: 99%

High resolution ensemble description of metamorphic and intrinsically disordered proteins using an efficient hybrid parallel tempering scheme

2021

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“…Thus, general protein force fields tend to overpopulate certain secondary structures or compact, collapsed structures over the extended ones [154]. Experimental structural data have been used to guide the development of novel or updated force fields for both all-atom and coarse-grained simulations, such as FF14IDPSFF [155], FF14IDP [156], FF99IDP [157], A99SB-ILDN [158], CHARMM36 IDPSFF [159], and AWSEM-IDP [160]. Third, the applied solvent model needs to be carefully selected as in IDPs, the solvation effect plays a greater role.…”

Section: Extremely Challenging Targets-intrinsically Disordered Proteinsmentioning

confidence: 99%

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

et al. 2020

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Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of how MD studies can give important insights into the dynamics and function of identified drug targets such as sirtuins, RAS proteins, or intrinsically disordered proteins. The role of MD in antibody design is also reviewed. In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate molecules for further development. The importance of considering the biological lipid bilayer environment in the MD simulations of membrane proteins is also discussed, using G-protein coupled receptors and ion channels as well as the drug-metabolizing cytochrome P450 enzymes as relevant examples. Lastly, we discuss the emerging role of MD simulations in facilitating the pharmaceutical formulation development of drugs and candidate drugs. Specifically, we look at how MD can be used in studying the crystalline and amorphous solids, the stability of amorphous drug or drug-polymer formulations, and drug solubility. Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple recent studies as examples. In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies.

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“…142 On the other side, Liu et al developed the CHARMM36IDPSFF, which showed an improvement over the CHARMM36 force eld in 18 IDPs, even though some limitations were found in the radius of gyration of large disordered proteins and the stability of fast-folding ones. 143 Lazar et al carried out 24-residue Ser/Arg-rich (SR22-45) MD simulations using CHARMM22* and CHARMM36. The histogram of R g distributions, compared to experimental data, showed a higher than real compactness in the CHARMM36 model, making the CHARMM22* force eld the way to go.…”

Section: Assisted Model Building With Energy Renement (Amber)mentioning

confidence: 99%

Folding and self-assembly of short intrinsically disordered peptides and protein regions

Argudo

Giner‐Casares

2021

Nanoscale Adv.

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Extensive tests and evaluation of the CHARMM36IDPSFF force field for intrinsically disordered proteins and folded proteins

Abstract: C36IDPSFF force field performs well in both disordered proteins and folded proteins, and achieves similar accuracy to a99SB-disp in relatively short-time simulations.

Cited by 41 publications

References 68 publications

High resolution ensemble description of metamorphic and intrinsically disordered proteins using an efficient hybrid parallel tempering scheme

High resolution ensemble description of metamorphic and intrinsically disordered proteins using an efficient hybrid parallel tempering scheme

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

Folding and self-assembly of short intrinsically disordered peptides and protein regions

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