Protein Science

Cover image for Vol. 26 Issue 7

Edited By: Brian W. Matthews

Impact Factor: 2.523

ISI Journal Citation Reports © Ranking: 2016: 158/286 (Biochemistry & Molecular Biology)

Online ISSN: 1469-896X

Proteins in Motion: Introduction to the Virtual Issue

Proteins in Motion
Introduction to the Virtual Issue
Lila M. Gierasch

Research on protein dynamics is far reaching and expanding. We have chosen in this Virtual Issue to gather papers into sub-themes under the overall theme of proteins in motion. We emphasize that this is a selection of contributions that have appeared in Protein Science on topics that fit under the proteins in motion theme. Necessarily, many important papers are not among those included in this Virtual Issue because of the constraints of space, and we apologize for that. Our goal was to illustrate some of the most exciting current areas of research on proteins in motion, along with examples of earlier research that laid the groundwork for current research. We hoped to pique readers’ interest and invite you to peruse the pages of Protein Science for more work in this significant area of protein research.


The fact that proteins are dynamic is widely accepted, but it is safe to say that methodologies to rigorously characterize protein motions have not undergone the same meteoric advances as those used to determine static atomic resolution protein structures, helped along by the many structural genomics initiatives such as the NIGMS-funded Protein Structure Initiative. Nonetheless, the quest to describe motions in proteins at many timescales has motivated many methodological advances. Thus, as our first sub-theme we have chosen methodology. Here, we include foundation papers on hydrogen exchange as monitored by mass spectrometry (1) and NMR (2); a key paper on molecular dynamics by Caves et al. (3) emphasizing the challenge of adequately sampling conformational space; and a signal paper by Ad Bax on alignment methods in NMR to extract structural and dynamic parameters (4). These landmark papers are accompanied by papers reporting recent applications of the methods reported in these earlier papers, such as the Skinner et al. (5) study of staphyloccal nuclease by hydrogen exchange, and development of new methods that yield insights into protein dynamics, such as novel chemical probes of local dynamics described by Stratton et al. (6), use of normal mode analysis to probe dynamics by Tsuchiya (7), and a powerful method to extract conformational state information from crystal structures by Lang et al (8).

Intrinsic dynamic properties of proteins

The ability of proteins to move is an intrinsic property of their sequence and structure. The next sub-theme, intrinsic dynamic properties of proteins, gathers papers that discuss the fundamental principles behind protein dynamics. Two seminal papers on entropy are included: one, a statistical mechanics treatment from Bromberg and Dill (9) and the other an NMR-based experimental approach from Li, Raychaudhuri and Wand (10). Five recent papers have been selected to illustrate a variety of methods and systems where fundamental dynamics properties were unveiled: Bhardwaj et al. (11) present DynaSIN, a Dynamic STructurl Interaction Network resulting from use of molecular network approach to dissect dynamic conformational changes from 3D structural data; Schmidt and Lamzin (12) show how anisotropic atomic displacement parameters in protein structural data can be used to derive dynamics; Rehm and coworkers (13) apply molecular dynamics to analyze a lid opening dynamic motion in lipases; Ho and Agard (14) present a method, Rotamerically Induced Perturbation (RIP) to extract coupling patterns embedded in protein structures that reveal dynamic modules that may mediate allostery; and Jimenez et al. (15) monitor loop mobility in a membrane protein using site-directed spin labeling (SDSL) and show that sensitivity to osmolytes reports on conformational equilibria.

Folding and aggregation

Exploration of conformational space is central to protein folding. Concomitantly, dynamic sampling of conformational states enables this exploration. Hence, protein dynamics are tightly linked to protein folding, as illustrated by the selected papers in the next sub-theme of this Virtual Issue: folding and aggregation. First, two landmark papers are included, one from Karplus and Weaver (16) on the diffusion-collision model of protein folding and comparisons of its predictions with experimental findings, and the other from Dill (17) discussing lessons from polymer principles that elucidate protein folding. Five more recent papers are included: Williams and Toon (18) show how an elastic network model can be used to explore protein folding pathways; Pais et al. (19) report that mannosylglycerate stabilizes staphylococcal nuclease by damping its dynamics; Fu et al. (20) discuss the importance of ΔCP and the denatured state to protein stability. Interestingly, the other two of the recent papers relate the conformational properties of two proteins, transthyretin and immunoglobulins to aggregation propensities, in one case in intermediate states (21) and in the other in the aggregates themselves (22). Binding and catalysis Protein dynamics underlies the mechanisms of binding and catalysis, the next sub-theme we have chosen. A number of exciting papers have appeared recently in Protein Science, and we accompany them by two earlier papers, both from the Nussinov group. One by Kumar et al. (23) explores how proteins may respond to binding by virtue of theis dynamic landscapes, and the other, by Ma et al. (24), discusses how conformational dynamics may account for the observation that proteins with specificity can also bind a variety of ligands. These topics are visited in the more recent papers selected for inclusion under this sub-theme. Dasgupta et al. (25) explore the relationship of ligand and self-coupled motions in ubiquitin and how they may explain its properties. Meireles et al. (26) relate intrinsic modes of motion characterized by normal mode analysis to the ligand binding properties of proteins. Moorman et al. (27) use NMR relaxation methods to investigate how the dynamics of lysozyme are impacted by binding to a carbohydrate ligand and relate the results to binding entropy. Gerek and Ozkan (28) present an approach based on replica exchange molecular dynamics (REMD) combined with normal mode analysis to explore protein binding site flexibility, using PDZ domains as a test case. Allostery The last topic, allostery, is having a 50th anniversary, as discussed in a recent commentary in Protein Science by Changeux (29), a father of the Monod-Wyman-Changeux allosteric model. The linkages of protein dynamics and allostery are deep and fascinating, illustrated by two key papers included to set the stage for this sub-theme: one, by Cui and Karplus (30) discusses the relationsip of allostery and cooperativity, and the other, by Dima and Thiramulai (31), shows how sequence analysis can shed light on allosteric networks. Recent papers gathered in this Virtual Issue exemplify the reach to larger multidomain proteins in current research on allosteric mechanisms. Chuang et al. (32) use computational solvent mapping to find domain-domain interfaces and hinges and reveal rigid body movements. The next two papers set up and interesting comparison: Street et al. (33) harness osmolytes to expose conformational changes in a large multidomain chaperone, Hsp90, and Fenton et al. (34) issue a caution about the use of osmolytes to support conformational equilibria in allostery based on their work with pyruvate kinase. We hope that this extravaganza comprised of a mixture of well-seasoned publications and hot, new papers from Protein Science on the fascinating topic of proteins in motion will stimulate new thinking and new research directions.


1. Zhang ZQ, Smith DL (1993) Determination of amide hydrogen-exchange by mass-spectrometry - a new tool for protein-structure elucidation. Protein Sci 2:522-531.

2. Milne JS, Mayne L, Roder H, Wand AJ, Englander SW (1998) Determinants of protein hydrogen exchange studied in equine cytochrome c. Protein Sci 7:739-745.

3. Caves LSD, Evanseck JD, Karplus M (1998) Locally accessible conformations of proteins: Multiple molecular dynamics simulations of crambin. Protein Sci 7:649-666.

4. Bax A (2003) Weak alignment offers new NMR opportunities to study protein structure and dynamics. Protein Sci 12:1-16.

5. Skinner JJ, Lim WK, Bedard S, Black BE, Englander SW (2012) Protein dynamics viewed by hydrogen exchange. Protein Sci 21:996-1005.

6. Stratton MM, Cutler TA, Ha J-H, Loh SN (2010) Probing local structural fluctuations in myoglobin by size-dependent thiol-disulfide exchange. Protein Sci 19:1587-1594.

7. Tsuchiya Y, Kinoshita K, Endo S, Wako H (2012) Dynamic features of homodimer interfaces calculated by normal-mode analysis. Protein Sci 21:1503-1513.

8. Lang PT, Ng H-L, Fraser JS, Corn JE, Echols N, Sales M, Holton JM, Alber T (2010) Automated electron-density sampling reveals widespread conformational polymorphism in proteins. Protein Sci 19:1420-1431.

9. Bromberg S, Dill KA (1994) Side-chain entropy and packing in proteins. Protein Sci 3:997-1009.

10. Li ZG, Raychaudhuri S, Wand AJ (1996) Insights into the local residual entropy of proteins provided by NMR relaxation. Protein Sci 5:2647-2650.

11. Bhardwaj N, Abyzov A, Clarke D, Shou C, Gerstein MB (2011) Integration of protein motions with molecular networks reveals different mechanisms for permanent and transient interactions. Protein Sci 20:1745-1754.

12. Schmidt A, Lamzin VS (2010) Internal motion in protein crystal structures. Protein Sci 19:944-953.

13. Rehm S, Trodler P, Pleuss J (2010) Solvent-induced lid opening in lipases: A molecular dynamics study. Protein Sci 19:2122-2130.

14. Ho BK, Agard DA (2010) Conserved tertiary couplings stabilize elements in the PDZ fold, leading to characteristic patterns of domain conformational flexibility. Protein Sci 19:398-411.

15. Jimenez RHF, Do Cao M-A, Kim M, Cafisco DS (2010) Osmolytes modulate conformational exchange in solvent-exposed regions of membrane proteins. Protein Sci 19:269-278.

16. Karplus M, Weaver DL (1994) Protein-folding dynamics – The diffusion-collision model and experimental-data. Protein Sci 3:650-668.

17. Dill KA (1999) Polymer principles and protein folding. Protein Sci 8:1166-1180.

18. Williams G, Toon AJ (2010) Protein folding pathways and state transitions described by classical equations of motion of an elastic network model. Protein Sci 19:2451-2461.

19. Pais TM, Lamosa P, Matzapetakis M, Turner DL, Santos H (2012) Mannosylglycerate stabilizes staphylococcal nuclease with restriction of slow beta-sheet motions. Protein Sci 21:1126-1137.

20. Fu H, Grimsley G, Scholtz JM, Pace CN (2010) Increasing protein stability: Importance of Delta C-p and the denatured state. Protein Sci 19:1044-1052.

21. Rodrigues JR, Simoes CJV, Silva CG, Brito RMM (2010) Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: Insights from molecular dynamics simulations. Protein Sci 19:202-219.

22. Franey H, Brych SR, Kolvenbach CG, Rajan RS (2010) Increased aggregation propensity of IgG2 subclass over IgG1: Role of conformational changes and covalent character in isolated aggregates. Protein Sci 19:1601-1615.

23. Kumar S, Ma BY, Tsai CJ Sinha N, Nussinov R (2000) Folding and binding cascades: Dynamic landscapes and population shifts. Protein Sci 9:10-19.

24. Ma BY, Shatsky M, Wolfson HJ, Nussinov R (2002) Multiple diverse ligands binding at a single protein site: A matter of pre-existing populations. Protein Sci 11:184-197.

25. Dasgupta B, Nakamura H, Kinjo AR (2013) Counterbalance of ligand- and self-coupled motions characterizes multispecificity of ubiquitin. Protein Sci 22:168-178.

26. Meireles L, Gur M, Bakan A, Bahar I (2011) Pre-existing soft modes of motion uniquely defined by native contact topology facilitate ligand binding to proteins. Protein Sci 20:1645-1658.

27. Moorman VR, Valentine KG, Wang AJ (2012) The dynamical response of hen egg white lysozyme to the binding of a carbohydrate ligand. Protein Sci 21:1066-1073.

28. Gerek ZN, Ozkan SB (2010) A flexible docking scheme to explore the binding selectivity of PDZ domains. Protein Sci 19:914-928.

29. Changeux J-P (2011) 50th anniversary of the word "Allosteric." Protein Sci 20:1119-1124.

30. Cui Q, Karplus M (2008) Allostery and cooperativity revisited. Protein Sci 17:1295-1307.

31. Dima RI, Thirumalai D (2006) Determination of network of residues that regulate allostery in protein families using sequence analysis. Protein Sci 15:258-268.

32. Chuang G-Y, Mehra-Chaudhary R, Ngan C-H, Zerbe BS, Kozakov D, Vajda S, Beamer LJ (2010) Domain motion and interdomain hot spots in a multidomain enzyme. Protein Sci 19:1662-1672.

33. Street TO, Krukenberg KA, Rosgen J, Bolen DW, Agard DA (2010) Osmolyte-induced conformational changes in the Hsp90 molecular chaperone. Protein Sci 19:57-65.

34. Fenton AW, Johnson TA, Holyoak T (2010) The pyruvate kinase model system, a cautionary tale for the use of osmolyte perturbations to support conformational equilibria in allostery. Protein Sci 19:1796-1800.