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Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide.

ABSTRACT: Understanding structural transitions within macromolecules remains an important challenge in biochemistry, with important implications for drug development and medicine. Insight into molecular behavior often requires residue-specific dynamics measurement at micromolar concentrations. We studied MP01-Gen4, a library peptide selected to rapidly undergo bioconjugation, by using electron paramagnetic resonance (EPR) to measure conformational dynamics. We mapped the dynamics of MP01-Gen4 with residue-specificity and identified the regions involved in a structural transformation related to the conjugation reaction. Upon reaction, the conformational dynamics of residues near the termini slow significantly more than central residues, indicating that the reaction induces a structural transition far from the reaction site. Arrhenius analysis demonstrates a nearly threefold decrease in the activation energy of conformational diffusion upon reaction (8.0?k_BT to 3.4?k_BT), which occurs across the entire peptide, independently of residue position. This novel approach to EPR spectral analysis provides insight into the positional extent of disorder and the nature of the energy landscape of a highly reactive, intrinsically disordered library peptide before and after conjugation.

SUBMITTER: Lindemann WR

PROVIDER: S-EPMC7018720 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide.

Lindemann William R WR Evans Ethan D ED Mijalis Alexander J AJ Saouaf Olivia M OM Pentelute Bradley L BL Ortony Julia H JH

Scientific reports 20200213 1

Understanding structural transitions within macromolecules remains an important challenge in biochemistry, with important implications for drug development and medicine. Insight into molecular behavior often requires residue-specific dynamics measurement at micromolar concentrations. We studied MP01-Gen4, a library peptide selected to rapidly undergo bioconjugation, by using electron paramagnetic resonance (EPR) to measure conformational dynamics. We mapped the dynamics of MP01-Gen4 with residue ...[more]

PMID: 32054898

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Project description:Technical strategies like amino acid substitution and residue modification have been widely used to characterize the importance of key amino acids and the role that each residue plays in the structural and functional properties of protein molecules. However, there is no systematic approach to assess the impact of the substituted/modified amino acids on the conformational dynamics of proteins. In this investigation to clarify the effects of residue modifications on the structural dynamics of human prion protein (PrP), a comparative molecular dynamics simulation study on the native and the amino acid-substituted analog at position 208 of PrP has been performed. It is believed that Arginine to Histidine mutation at position 208 is responsible for the structural transition of the native form of human prion protein to the pathogenic isoform causing Creutzfeldt-Jakob disease (CJD). So, three 10 ns molecular dynamics simulations on three model constructs have been performed. Simulation results indicated considerable differences of conformational fluctuations for Alanine substituted construct (PrPALA) and the analog form (PrPSB) comprising the neutralized state of the Arginine residue at position 208 of the human prion protein. According to our data, substitution of the Arginine residue by the uncharged state of this residue induces some reversible structural alterations in the intrinsically flexible loop area including residues 167-171 of PrP. Thus, deprotonation of Arg(208) is a weak perturbation to the structural fluctuations of the protein backbone and the resulting construct behaves almost identical as its native form. Otherwise, Alanine substitution at position 208 imposed an irreversible impact on the secondary and tertiary structure of the protein, which leads to conformational instabilities in the remote hot region comprising residues 190-195 of the C-terminal part of helix 2. Based on the results, it could be deduced that the observed conformational transitions upon Arg(208) to His point mutation, which is the main reason for CJD, may be mainly related to the structural instabilities due to the induced-conformational changes that caused alterations in local/spatial arrangements of the force distributions in the backbone of the human prion protein.

Dataset Information

Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide.

Publications

Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide.

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