PPM: a side-chain and backbone chemical shift predictor for the assessment of protein conformational ensembles
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ARTICLE
PPM: a side-chain and backbone chemical shift predictor for the assessment of protein conformational ensembles Da-Wei Li • Rafael Bru¨schweiler
Received: 19 June 2012 / Accepted: 31 August 2012 / Published online: 13 September 2012 Springer Science+Business Media B.V. 2012
Abstract The combination of the wide availability of protein backbone and side-chain NMR chemical shifts with advances in understanding of their relationship to protein structure makes these parameters useful for the assessment of structural-dynamic protein models. A new chemical shift predictor (PPM) is introduced, which is solely based on physical–chemical contributions to the chemical shifts for both the protein backbone and methyl-bearing amino-acid side chains. To explicitly account for the effects of protein dynamics on chemical shifts, PPM was directly refined against 100 ns long molecular dynamics (MD) simulations of 35 proteins with known experimental NMR chemical shifts. It is found that the prediction of methyl-proton chemical shifts by PPM from MD ensembles is improved over other methods, while backbone Ca, Cb, C0 , N, and HN chemical shifts are predicted at an accuracy comparable to the latest generation of chemical shift prediction programs. PPM is particularly suitable for the rapid evaluation of large protein conformational ensembles on their consistency with experimental NMR data and the possible improvement of protein force fields from chemical shifts. Keywords NMR chemical shift prediction Side-chain methyl groups Protein backbone
Electronic supplementary material The online version of this article (doi:10.1007/s10858-012-9668-8) contains supplementary material, which is available to authorized users. D.-W. Li R. Bru¨schweiler (&) Chemical Sciences Laboratory, Department of Chemistry and Biochemistry and National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL 32306, USA e-mail: [email protected]
Introduction Chemical shifts represent the most accurate and most ubiquitous NMR information of proteins. For many proteins the resonance assignments, and hence the assigned chemical shifts, are the sole source of NMR information readily available via the BioMagResDataBank (BMRB) (Ulrich et al. 2008), which presently includes chemical shifts of over 5,000 proteins. In spite of their complex dependence on protein structure, significant progress has been made over the years in the prediction of chemical shifts from protein structures using a variety of strategies implemented in software, such as Shifts (Xu and Case 2001, 2002), ShiftX?/ShiftX2 (Neal et al. 2003; Han et al. 2011), SPARTA/SPARTA? (Shen and Bax 2007, 2010), CamShift (Kohlhoff et al. 2009), CH3shift (Sahakyan et al. 2011) and 4DSPOT (Lehtivarjo et al. 2009, 2012). These programs can be used for the validation and refinement of protein structures or the determination of average protein structures from chemical shifts alone (Cavalli et al. 2007; Shen et al. 2008, 2009; Rosato et al. 2012). At room temperature the experimen
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