5 years ago

Predicting Optimal DEER Label Positions to Study Protein Conformational Heterogeneity

Predicting Optimal DEER Label Positions to Study Protein Conformational Heterogeneity
Shriyaa Mittal, Diwakar Shukla
Double electron–electron resonance (DEER) spectroscopy is a powerful experimental technique for understanding the conformational heterogeneity of proteins. It involves attaching nitroxide spin labels to two residues in the protein to obtain a distance distribution between them. However, the choice of residue pairs to label in the protein requires careful thought, as experimentalists must pick label positions from a large set of all possible residue-pair combinations in the protein. In this article, we address the problem of the choice of DEER spin-label positions in a protein. For this purpose, we utilize all-atom molecular dynamics simulations of protein dynamics, to rank the sets of labeled residue pairs in terms of their ability to capture the conformational dynamics of the protein. Our design methodology is based on the following two criteria: (1) An ideal set of DEER spin-label positions should capture the slowest conformational-change processes observed in the protein dynamics, and (2) any two sets of residue pairs should describe orthogonal conformational-change processes to maximize the overall information gain and reduce the number of labeled residue pairs. We utilize Markov state models of protein dynamics to identify slow dynamical processes and a genetic-algorithm-based approach to predict the optimal choices of residue pairs with limited computational time requirements. We predict the optimal residue pairs for DEER spectroscopy in β2 adrenergic receptor, the C-terminal domain of calmodulin, and peptide transporter PepTSo. We find that our choices were ranked higher than those used to perform DEER experiments on the proteins investigated in this study. Hence, the predicted choices of DEER residue pairs determined by our method provide maximum insight into the conformational heterogeneity of the protein while using the minimum number of labeled residues.

Publisher URL: http://dx.doi.org/10.1021/acs.jpcb.7b04785

DOI: 10.1021/acs.jpcb.7b04785

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.