Enhancing the quality of protein conformation ensembles with relative populations
- 408 Downloads
The function and dynamics of many proteins are best understood not from a single structure but from an ensemble. A high quality ensemble is necessary for accurately delineating protein dynamics. However, conformations in an ensemble are generally given equal weights. Few attempts were made to assign relative populations to the conformations, mainly due to the lack of right experimental data. Here we propose a method for assigning relative populations to ensembles using experimental residue dipolar couplings (RDC) as constraints, and show that relative populations can significantly enhance an ensemble’s ability in representing the native states and dynamics. The method works by identifying conformation states within an ensemble and assigning appropriate relative populations to them. Each of these conformation states is represented by a sub-ensemble consisting of a subset of the conformations. Application to the ubiquitin X-ray ensemble clearly identifies two key conformation states, with relative populations in excellent agreement with previous work. We then apply the method to a reprotonated ERNST ensemble that is enhanced with a switched conformation, and show that as a result of population reweighting, not only the reproduction of RDCs is significantly improved, but common conformational features (particularly the dihedral angle distributions of ϕ 53 and ψ 52) also emerge for both the X-ray ensemble and the reprotonated ERNST ensemble.
KeywordsResidual dipolar couplings Ubiquitin Relative populations Boltzmann weights Weighted ensemble Ensemble quality
Funding from National Science Foundation (CAREER award, CCF-0953517) is gratefully acknowledged. The authors would also like to thank the two anonymous reviewers for their insightful comments.
- Lakomek NA, Walter KF, Fares C, Lange OF, de Groot BL, Grubmuller H, Bruschweiler R, Munk A, Becker S, Meiler J et al (2008) Self-consistent residual dipolar coupling based model-free analysis for the robust determination of nanosecond to microsecond protein dynamics. J Biomol NMR 41:139–155CrossRefGoogle Scholar
- Ottiger M, Bax A (1998) Determination of relative N-HN, N-C′, Cα-C′, and Cα-Hα effective bond lengths in a protein by NMR in a dilute liquid crystalline phase. J Am Chem Soc 120(47):12334–12341Google Scholar
- Phillips GN (2009) Describing protein conformational ensembles: beyond static snapshots. F1000 biology reports, vol 1Google Scholar