The aqueous environment as an active participant in the protein folding process

Gadzała, Małgorzata; Dułak, Dawid; Kalinowska, Barbara; Baster, Zbigniew; Bryliński, Michał; Konieczny, Leszek; Banach, Mateusz; Roterman, Irena

doi:10.1016/j.jmgm.2018.12.008

Cited by 9 publications

(7 citation statements)

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“…Another important milestone in de novo design had been passed. Given its relatively simple but cooperatively folded globular structure, α 3D quickly became a very widely studied protein for computational and experimental studies of protein folding (Zhu et al ., 2003; Park et al ., 2006; Liu et al ., 2009; Adhikari et al ., 2012; Shao, 2014; Chung et al ., 2015; Zeng et al ., 2016; Maruyama and Mitsutake, 2017; Walder et al ., 2017; Xiong et al ., 2017; Jumper et al ., 2018; Koebke et al ., 2018; Yoo et al ., 2018; Gadzala et al ., 2019). Its folding kinetics are among the most extensively characterized of small cooperatively folded proteins (Chung et al ., 2015).…”

Section: Computational Design Guided By Fundamental Physicochemical Pmentioning

confidence: 99%

De novoprotein design, a retrospective

Korendovych

DeGrado

2020

Quart. Rev. Biophys.

189

179

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Proteins are molecular machines whose function depends on their ability to achieve complex folds with precisely defined structural and dynamic properties. The rational design of proteins from first-principles, or de novo, was once considered to be impossible, but today proteins with a variety of folds and functions have been realized. We review the evolution of the field from its earliest days, placing particular emphasis on how this endeavor has illuminated our understanding of the principles underlying the folding and function of natural proteins, and is informing the design of macromolecules with unprecedented structures and properties. An initial set of milestones in de novo protein design focused on the construction of sequences that folded in water and membranes to adopt folded conformations. The first proteins were designed from first-principles using very simple physical models. As computers became more powerful, the use of the rotamer approximation allowed one to discover amino acid sequences that stabilize the desired fold. As the crystallographic database of protein structures expanded in subsequent years, it became possible to construct proteins by assembling short backbone fragments that frequently recur in Nature. The second set of milestones in de novo design involves the discovery of complex functions. Proteins have been designed to bind a variety of metals, porphyrins, and other cofactors. The design of proteins that catalyze hydrolysis and oxygen-dependent reactions has progressed significantly. However, de novo design of catalysts for energetically demanding reactions, or even proteins that bind with high affinity and specificity to highly functionalized complex polar molecules remains an importnant challenge that is now being achieved. Finally, the protein design contributed significantly to our understanding of membrane protein folding and transport of ions across membranes. The area of membrane protein design, or more generally of biomimetic polymers that function in mixed or non-aqueous environments, is now becoming increasingly possible.

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Section: Computational Design Guided By Fundamental Physicochemical Pmentioning

confidence: 99%

De novoprotein design, a retrospective

Korendovych

DeGrado

2020

Quart. Rev. Biophys.

189

179

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“…All calculations were carried out using online servers [29,30]. In addition, a separate calculation was performed using a software toolkit based on the FOD model (Jagiellonian University-Medical College, Krakow, Poland) [20][21][22], which, in addition to internal free energy optimization, also optimizes interactions with an external force field representing the aqueous solvent. This force field is mathematically defined as a 3D Gaussian and its presence results in internalization of hydrophobic residues, with the attendant exposure of hydrophilic residues on the protein surface.…”

Section: Obtaining Alternative Asyn Polypeptide Modelsmentioning

confidence: 99%

“…The base model has been thoroughly described in numerous publications [20][21][22]. At its core rests the assumption that a globular protein contains a hydrophobic core, which (in its "idealized" or "theoretical" version) can be mathematically modeled as a 3D Gaussian superimposed upon the protein body.…”

Section: Fuzzy Oil Drop Model-protein Folding With Preferential Genermentioning

confidence: 99%

“…The ASyn chain is sometimes divided into an N-terminal fragment (1-60), a NAC (non-amyloid beta component; 61-95) and a strongly hydrophilic C-terminal fragment (96-140) [5]. Another characteristic property of ASyn is the presence of imperfect KTKEGV repeats starting at positions 10,21,32,43,58,69, and 80, respectively. The first 25 residues of the N-terminal fragment are responsible for anchoring the protein in the lipid bilayer, whereas, residues 26-98 mediate affinity towards the membrane, depending on the composition of the membrane itself [6].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, we perform calculations based on the fuzzy oil drop model, enabling us to acknowledge the effects of an external force field (contributed by the aqueous solvent) in addition to internal force fields (atom-atom interactions). This external field directs hydrophobic residues to congregate at the center of the molecule, while promoting exposure of hydrophilic residues [20][21][22]. Consequently, it favors the formation of a globular protein.…”

Section: Introductionmentioning

confidence: 99%

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Alternative Structures of α-Synuclein

et al. 2020

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The object of our analysis is the structure of alpha-synuclein (ASyn), which, under in vivo conditions, associates with presynaptic vesicles. Misfolding of ASyn is known to be implicated in Parkinson’s disease. The availability of structural information for both the micelle-bound and amyloid form of ASyn enables us to speculate on the specific mechanism of amyloid transformation. This analysis is all the more interesting given the fact that—Unlike in Aβ(1–42) amyloids—only the central fragment (30–100) of ASyn has a fibrillar structure, whereas, its N- and C-terminal fragments (1–30 and 100–140, respectively) are described as random coils. Our work addresses the following question: Can the ASyn chain—as well as the aforementioned individual fragments—adopt globular conformations? In order to provide an answer, we subjected the corresponding sequences to simulations carried out using Robetta and I-Tasser, both of which are regarded as accurate protein structure predictors. In addition, we also applied the fuzzy oil drop (FOD) model, which, in addition to optimizing the protein’s internal free energy, acknowledges the presence of an external force field contributed by the aqueous solvent. This field directs hydrophobic residues to congregate near the center of the protein body while exposing hydrophilic residues on its surface. Comparative analysis of the obtained models suggests that fragments which do not participate in forming the amyloid fibril (i.e., 1–30 and 100–140) can indeed attain globular conformations. We also explain the influence of mutations observed in vivo upon the susceptibility of ASyn to undergo amyloid transformation. In particular, the 30–100 fragment (which adopts a fibrillar structure in PDB) is not predicted to produce a centralized hydrophobic core by any of the applied toolkits (Robetta, I-Tasser, and FOD). This means that in order to minimize the entropically disadvantageous contact between hydrophobic residues and the polar solvent, ASyn adopts the form of a ribbonlike micelle (rather than a spherical one). In other words, the ribbonlike micelle represents a synergy between the conformational preferences of the protein chain and the influence of its environment.

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