Molecular Dynamics Simulation to Uncover the Mechanisms of Protein Instability During Freezing

Duran, Tibo; Minatovicz, Bruna; Bai, Jun; Shin, Dongkwan; Mohammadiarani, Hossein; Chaudhuri, Bodhisattwa

doi:10.1016/j.xphs.2021.01.002

Cited by 25 publications

(22 citation statements)

References 75 publications

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“…Moreover, they further provided the basis for the binding mode of small-molecule ligands and receptor proteins. 21 All MD simulations in the current work used the GROMACS (version 19.5) with the GROMACS96 43a1 force field. 22 Dundee PRODRG2.5 server was used to generate the topological parameters of small molecules.…”

Section: Methodsmentioning

confidence: 99%

Molecular Simulation Study on the Interaction between Tyrosinase and Flavonoids from Sea Buckthorn

Guo

Lian

et al. 2021

ACS Omega

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Isorhamnetin, kaempferol, myricetin, and quercetin are four kinds of secondary metabolites in sea buckthorn, which have a wide range of biological activities. Investigating their interactions with tyrosinase at the atomic level can improve the bioavailability of sea buckthorn. Both molecular docking and molecular dynamics simulation methods were employed to study the interactions of these ligands with tyrosinase. The results of molecular docking indicated that these four small molecules such as isorhamnetin, kaempferol, myricetin, and quercetin can all dock into the active center of tyrosinase, and by occupying the active site, they can prevent substrate binding, thereby reducing the catalytic activity of tyrosinase. Molecular dynamics simulation trajectory analysis showed that all tyrosinase–ligand complexes reach an equilibrium within 100 ns. In addition, quercetin has the lowest binding energy among these four ligands, and the complex with tyrosinase is the most stable. This study not only provides valuable information for improving the bioavailability of sea buckthorn but also contributes to the discovery of effective natural inhibitors of tyrosinase.

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Section: Methodsmentioning

confidence: 99%

Molecular Simulation Study on the Interaction between Tyrosinase and Flavonoids from Sea Buckthorn

Guo

Lian

et al. 2021

ACS Omega

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“…As such, they have been successfully applied to study various protein phenomena in crowded environments such as the kinetics and thermodynamics of protein conformational changes, 20 early stages of protein aggregation in peptides and small proteins, 6 protein–protein/excipient interactions, 21 among other processes. 22 , 23 …”

Section: Types Of Protein Modelsmentioning

confidence: 99%

Computational models for studying physical instabilities in high concentration biotherapeutic formulations

Blanco

2022

mAbs

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Computational prediction of the behavior of concentrated protein solutions is particularly advantageous in early development stages of biotherapeutics when material availability is limited and a large set of formulation conditions needs to be explored. This review provides an overview of the different computational paradigms that have been successfully used in modeling undesirable physical behaviors of protein solutions with a particular emphasis on high-concentration drug formulations. This includes models ranging from all-atom simulations, coarse-grained representations to macro-scale mathematical descriptions used to study physical instability phenomena of protein solutions such as aggregation, elevated viscosity, and phase separation. These models are compared and summarized in the context of the physical processes and their underlying assumptions and limitations. A detailed analysis is also given for identifying protein interaction processes that are explicitly or implicitly considered in the different modeling approaches and particularly their relations to various formulation parameters. Lastly, many of the shortcomings of existing computational models are discussed, providing perspectives and possible directions toward an efficient computational framework for designing effective protein formulations.

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“…For example, denaturation of proteins at the ice-liquid interface has been reported for many proteins (33,34). Another consequence of the ice formation is the freeze concentration of all solutes remaining in the unfrozen solution, including proteins (35,36). Apart from the up-concentration of solutes, which may accelerate bimolecular reactions leading to protein aggregation, phase separation may also occur as a consequence of freeze concentration (37).…”

Section: Effect Of Processing Conditions On Protein Stabilitymentioning

confidence: 99%

Use of a Design of Experiments (DoE) Approach to Optimize Large-Scale Freeze-Thaw Process of Biologics

2021

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Large volumes of protein solutions are commonly stored in a frozen state before further drug product fill and finish. This study aimed to establish a design space to perform large-scale freeze-thaw (F/T) processes of biotherapeutics without inducing protein destabilization. A response surface model was designed to evaluate the following main factors and interactions: fill volume of the protein solution in 1-L containers, distance among nine containers during both F/T, freezer set temperature, and a novel forced air flow methodology during thawing. The analysis from 46 experimental runs indicated over 4-fold increase in the freezing rate by lowering the freezing temperature from −20 to −80°C, and the forced air flow at 98 fpm doubled the thawing rate. Furthermore, multivariate linear regression modeling revealed the significant impact of all main factors investigated on lactate dehydrogenase (LDH) quality attributes. The factor that most strongly affected the retention of LDH activity was the loading distance: ≥ 5 cm among containers positively affected the LDH activity response in 50.6%. The factor that most strongly retained the LDH tetramers was the set freezer temperature towards the lower range of −80°C (2.2% higher tetramer retention compared to −20°C freezing, due to faster freezing rate). In summary, this DoEbased systematic analysis increased F/T process understanding at large scale, identified critical F/T process parameters, and confirmed the feasibility of applying faster freezing and forced air thawing procedures to maintain the stability of LDH solutions subject to largescale F/T.

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Molecular Dynamics Simulation to Uncover the Mechanisms of Protein Instability During Freezing

Cited by 25 publications

References 75 publications

Molecular Simulation Study on the Interaction between Tyrosinase and Flavonoids from Sea Buckthorn

Molecular Simulation Study on the Interaction between Tyrosinase and Flavonoids from Sea Buckthorn

Computational models for studying physical instabilities in high concentration biotherapeutic formulations

Use of a Design of Experiments (DoE) Approach to Optimize Large-Scale Freeze-Thaw Process of Biologics

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