TY - JOUR
T1 - Predicting Optimal DEER Label Positions to Study Protein Conformational Heterogeneity
AU - Mittal, Shriyaa
AU - Shukla, Diwakar
N1 - Funding Information:
The authors thank the Blue Waters Sustained-Petascale Computing Project, which is supported by the National Science Foundation (Awards OCI-0725070 and ACI-1238993) and the state of Illinois. The authors also thank D. E. Shaw Research and Pande Lab at Stanford University for MD simulation trajectories of β2 adrenergic receptor and calmodulin, respectively. S.M. is supported by the CSE Fellows Program, Computational Science and Engineering at University of Illinois, Urbana−Champaign, Urbana, IL.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/10/26
Y1 - 2017/10/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85032631802&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85032631802&partnerID=8YFLogxK
U2 - 10.1021/acs.jpcb.7b04785
DO - 10.1021/acs.jpcb.7b04785
M3 - Article
C2 - 28726404
AN - SCOPUS:85032631802
SN - 1520-6106
VL - 121
SP - 9761
EP - 9770
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 42
ER -