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Full Atom Simulations of Spin Label Conformations.

ABSTRACT: Interpretation of EPR measurables from spin labels in terms of structure and dynamics requires knowledge of label behavior. General strategies were developed for simulation of labels used in EPR of proteins. The criteria for those simulations are (a) exhaustive sampling of rotamer space, (b) consensus of results independent of starting points, and (c) inclusion of entropy. These criteria are satisfied only when the number of transitions in any dihedral angle exceeds 100 and the simulation maintains thermodynamic equilibrium. Methods such as conventional MD do not efficiently cross energetic barriers, simulated anealing, Monte Carlo or popular Rotamer Library methodologies are potential energy based and ignore entropy (in addition to their specific shortcomings: environment fluctuations, fixed environment, or electrostatics). The Simulated scaling method avoids the above flaws by modulating the force fields between a reduced (allowing crossing energy barriers) and full potential (sampling minima). Spin label diffuses on this surface while remaining in thermodynamic equilibrium. Simulations show that (a) adopting a single conformation is rare, often there are two to four populated rotamers and (b) position of the NO varies up to 16 Å. These results illustrate necessity for caution when interpreting EPR signals in terms of molecular structure. For example, the 10-16 Å distance change in DEER should not be interpreted as a large conformational change, it can well be a flip about C?-C? bond. Rigorous exploration of possible rotamer structures of a spin label is paramount in signal interpretation. We advocate use of bifunctional labels, motion of which is restricted 10,000-fold and the NO position is restricted to 2-5 Å.

SUBMITTER: Fajer P

PROVIDER: S-EPMC4959449 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Full Atom Simulations of Spin Label Conformations.

Fajer Piotr P Fajer Mikolai M Zawrotny Michael M Yang Wei W

Methods in enzymology 20150911

Interpretation of EPR measurables from spin labels in terms of structure and dynamics requires knowledge of label behavior. General strategies were developed for simulation of labels used in EPR of proteins. The criteria for those simulations are (a) exhaustive sampling of rotamer space, (b) consensus of results independent of starting points, and (c) inclusion of entropy. These criteria are satisfied only when the number of transitions in any dihedral angle exceeds 100 and the simulation mainta ...[more]

PMID: 26478501

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Project description:Amyloidlike fibrils are found in many fatal diseases, including Alzheimer's disease, type II diabetes mellitus, transmissible spongiform encephalopathies, and prion diseases. These diseases are linked to proteins that have partially unfolded, misfolded, and aggregated into amyloidlike fibrils. The kinetics of amyloidlike fibrils aggregation is still hotly debated and remains an important open question. We have utilized the GNNQQNY crystal structure and high-temperature molecular dynamics simulation in explicit solvent to study the disaggregation mechanism of the GNNQQNY fibrils and to infer its likely aggregation pathways. A hexamer model and a 12-mer model both with two parallel beta-sheets separated by a dry side-chain interface were adopted in our computational analysis. A cumulative time of 1 micros was simulated for the hexamer model at five different temperatures (298 K, 348 K, 398 K, 448 K, and 498 K), and a cumulative time of 2.1 micros was simulated for the 12-mer model at four temperatures (298 K, 398 K, 448 K, and 498 K). Our disaggregation landscape and kinetics analyses indicate that tetramers probably act as the transition state in both the hexamer and the 12-mer simulations. In addition, the 12-mer simulations show that the initial aggregation nucleus is with eight peptides. Furthermore, the landscape is rather flat from 8-mers to 12-mers, indicating the absence of major barriers once the initial aggregation nucleus forms. Thus, the likely aggregation pathway is from monomers to the initial nucleus of 8-mers with tetramers as the transition state. Transition state structure analysis shows that the two dominant transition state conformations are tetramers in the 3-1 and 2-2 arrangements. The predominant nucleus conformations are in peptide arrangements maximizing dry side-chain contacts. Landscape and kinetics analyses also indicate that the parallel beta-sheets form earlier than the dry side-chain contacts during aggregation. These results provide further insights in understanding the early fibrils aggregation.

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Full Atom Simulations of Spin Label Conformations.

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Full Atom Simulations of Spin Label Conformations.

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