Aggrescan4D: structure-informed analysis of pH-dependent protein aggregation

Bárcenas, Oriol; Kuriata, Aleksander; Zalewski, Mateusz; Iglesias, Valentín; Pintado-Grima, Carlos; Firlik, Grzegorz; Burdukiewicz, Michał; Kmiecik, Sebastian; Ventura, Salvador

doi:10.1093/nar/gkae382

Cited by 8 publications

References 41 publications

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Exploring protein functions from structural flexibility using CABS‐flex modeling

Nithin,

Fornari,

Pilla

et al. 2024

Protein Science

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Understanding protein function often necessitates characterizing the flexibility of protein structures. However, simulating protein flexibility poses significant challenges due to the complex dynamics of protein systems, requiring extensive computational resources and accurate modeling techniques. In response to these challenges, the CABS‐flex method has been developed as an efficient modeling tool that combines coarse‐grained simulations with all‐atom detail. Available both as a web server and a standalone package, CABS‐flex is dedicated to a wide range of users. The web server version offers an accessible interface for straightforward tasks, while the standalone command‐line program is designed for advanced users, providing additional features, analytical tools, and support for handling large systems. This paper examines the application of CABS‐flex across various structure–function studies, facilitating investigations into the interplay among protein structure, dynamics, and function in diverse research fields. We present an overview of the current status of the CABS‐flex methodology, highlighting its recent advancements, practical applications, and forthcoming challenges.

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Exploring protein functions from structural flexibility using CABS‐flex modeling

Nithin,

Fornari,

Pilla

et al. 2024

Protein Science

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Insight Into Factors Influencing the Aggregation Process in Wild‐Type and P66R Mutant SOD1: Computational and Spectroscopic Approaches

Farrokhzad,

Seyedalipour,

Baziyar

et al. 2024

Proteins

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Disturbances in metal ion homeostasis associated with amyotrophic lateral sclerosis (ALS) have been described for several years, but the exact mechanism of involvement is not well understood. To elucidate the role of metalation in superoxide dismutase (SOD1) misfolding and aggregation, we comprehensively characterized the structural features (apo/holo forms) of WT‐SOD1 and P66R mutant in loop IV. Using computational and experimental methodologies, we assessed the physicochemical properties of these variants and their correlation with protein aggregation at the molecular level. Modifications in apo‐SOD1 compared to holo‐SOD1 were more pronounced in flexibility, stability, hydrophobicity, and intramolecular interactions, as indicated by molecular dynamics simulations. The enzymatic activities of holo/apo‐WT SOD1 were 1.30 and 1.88‐fold of the holo/apo P66R mutant, respectively. Under amyloid‐inducing conditions, decreased ANS fluorescence intensity in the apo‐form relative to the holo‐form suggested pre‐fibrillar species and amyloid aggregate growth due to occluded hydrophobic pockets. FTIR spectroscopy revealed that apo‐WT‐SOD1 and apo‐P66R exhibited a mixture of parallel and intermolecular β‐sheet structures, indicative of aggregation propensity. Aggregate species were identified using TEM, Congo red staining, and ThT/ANS fluorescence spectroscopy. Thermodynamic analyses with GdnHCl demonstrated that metal deficit, mutation, and intramolecular disulfide bond reduction are essential for initiating SOD1 misfolding and aggregation. These disruptions destabilize the dimer‐monomer equilibrium, promoting dimer dissociation into monomers and decreasing the thermodynamic stability of SOD1 variants, thus facilitating amyloid/amorphous aggregate formation. Our findings offer novel insights into protein aggregation mechanisms in disease pathology and highlight potential therapeutic strategies against toxic protein aggregation, including SOD1.

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A comprehensive overview of recent advances in generative models for antibodies

Meng,

Zhou,

et al. 2024

Computational and Structural Biotechnology Journal

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Aggrescan4D: structure-informed analysis of pH-dependent protein aggregation

Cited by 8 publications

References 41 publications

Exploring protein functions from structural flexibility using CABS‐flex modeling

Exploring protein functions from structural flexibility using CABS‐flex modeling

Insight Into Factors Influencing the Aggregation Process in Wild‐Type and P66R Mutant SOD1: Computational and Spectroscopic Approaches

A comprehensive overview of recent advances in generative models for antibodies

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