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Simple MD-based model for oxidative folding of peptides and proteins.

ABSTRACT: Significant strides have been recently made to fold peptides and small proteins in silico using MD simulations. However, facilities are currently lacking to include disulfide bonding in the MD models of protein folding. To address this problem, we have developed a simple empirical protocol to model formation of disulfides, which is perturbation-free, retains the same speed as conventional MD simulations and allows one to control the reaction rate. The new protocol has been tested on 15-aminoacid peptide guanylin containing four cysteine residues; the net simulation time using Amber ff14SB force field was 61??s. The resulting isomer distribution is in qualitative agreement with experiment, suggesting that oxidative folding of guanylin in vitro occurs under kinetic control. The highly stable conformation of the so-called isomer 2(B) has been obtained for full-length guanylin, which is significantly different from the poorly ordered structure of the truncated peptide PDB ID 1GNB. In addition, we have simulated oxidative folding of guanylin within the 94-aminoacid prohormone proguanylin. The obtained structure is in good agreement with the NMR coordinates 1O8R. The proposed modeling strategy can help to explore certain fundamental aspects of protein folding and is potentially relevant for manufacturing of synthetic peptides and recombinant proteins.

SUBMITTER: Izmailov SA

PROVIDER: S-EPMC5570944 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Simple MD-based model for oxidative folding of peptides and proteins.

Izmailov Sergei A SA Podkorytov Ivan S IS Skrynnikov Nikolai R NR

Scientific reports 20170824 1

Significant strides have been recently made to fold peptides and small proteins in silico using MD simulations. However, facilities are currently lacking to include disulfide bonding in the MD models of protein folding. To address this problem, we have developed a simple empirical protocol to model formation of disulfides, which is perturbation-free, retains the same speed as conventional MD simulations and allows one to control the reaction rate. The new protocol has been tested on 15-aminoacid ...[more]

PMID: 28839177

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Project description:The ability of many proteins to convert from their functional soluble state to amyloid fibrils can be attributed to inter-molecular beta strand formation. Such amyloid formation is associated with neurodegenerative disorders like Alzheimer's and Parkinson's. Molecular modelling can play a key role in providing insight into the factors that make proteins prone to fibril formation. However, fully atomistic models are computationally too expensive to capture the length and time scales associated with fibril formation. As the ability to form fibrils is the rule rather than the exception, much insight can be gained from the study of coarse-grained models that capture the key generic features associated with amyloid formation. Here we present a simple lattice model that can capture both protein folding and beta strand formation. Unlike standard lattice models, this model explicitly incorporates the formation of hydrogen bonds and the directionality of side chains. The simplicity of our model makes it computationally feasible to investigate the interplay between folding, amorphous aggregation and fibril formation, and maintains the capability of classic lattice models to simulate protein folding with high specificity. In our model, the folded proteins contain structures that resemble naturally occurring beta-sheets, with alternating polar and hydrophobic amino acids. Moreover, fibrils with intermolecular cross-beta strand conformations can be formed spontaneously out of multiple short hydrophobic peptide sequences. Both the formation of hydrogen bonds in folded structures and in fibrils is strongly dependent on the amino acid sequence, indicating that hydrogen-bonding interactions alone are not strong enough to initiate the formation of beta sheets. This result agrees with experimental observations that beta sheet and amyloid formation is strongly sequence dependent, with hydrophobic sequences being more prone to form such structures. Our model should open the way to a systematic study of the interplay between the factors that lead to amyloid formation.

Dataset Information

Simple MD-based model for oxidative folding of peptides and proteins.

Publications

Simple MD-based model for oxidative folding of peptides and proteins.

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