oa Editorial [Hot Topic: Protein Folding Dynamics (Guest Editor: Dr. Ruhong Zhou)]

Protein Folding Dynamics: Bridging the Gap Between Theory and Experiments Once regarded as a grand challenge, protein folding has seen great progress in recent years [1-3], and the gap between the timescales reachable by experiments and by computer simulations has been significantly reduced due to concurrent advances in both experimental [4-7] and theoretical techniques [8-10]. Scientists can nowadays access to the microseconds-to-milliseconds timescale, which is sufficient to characterize the folding dynamics of many important proteins [11-14]. When observed at such a high resolution, folding appears to be a complicated kinetic network of transitions among several intermediate states [15, 16], defying simple descriptions of the mechanism. Even when simple exponential kinetics is observed, it does not necessarily imply a simple one-route two-state folding pathway [15]. Different folding and unfolding pathways often coexist, whose likelihood is affected by factors like temperature, pH, pressure, denaturants, and so on. Nanoscale dewetting (water drying) can also play a significant role in the protein folding kinetics [17, 18]. Still, driving forces are at work, albeit weak, which drive the conformational changes toward the native state avoiding the never-ending random search envisaged by Levinthal's paradox. The elucidation of such driving forces is one of the fields where protein folding simulations can greatly help the interpretation of experiments. The aim of the current hot topic special issue is to put into perspective the latest developments, and to identify the most promising routes which could lead to a deeper understanding of protein folding. Thanks to all the contributing authors, the current special issue covers many aspects of protein folding, from both the experimental and theoretical point of views. To name a few, Caflisch and Hamm use both IR spectroscopy and molecular dynamics simulations to study the folding of photoswitchable α-helices. The folding kinetics of these peptides is profoundly non-exponential, which is attributed to a partitioning of the unfolded state into several misfolded traps. These traps are connected to the folded state in a hub-like fashion with folding barriers of different heights. Laio and coworkers propose a bias-exchange metadynamics (BE-META) method to efficiently sample the protein conformation space and reconstruct the folding free energy landscape. Similarly, Okmato and coworkers have extended the generalized-ensembles for efficient conformation space sampling. Peti and coworkers have studied the interesting “folding upon binding” problem (intrinsically disordered proteins) using NMR experiments. These intrinsically disordered but biologically active proteins exist in many biological systems and play critical roles in multiple protein regulatory processes. While disordered in their unbound states, these proteins often fold upon binding with their interaction partners. Peti et al. particularly discuss how Protein Phosphatase 1 (PP1) folds upon binding with its peptide ligands. Jackson, on the other hand, has examined extensively another interesting class of proteins, the knotted proteins, with various experimental techniques. There are now at least 300 protein structures deposited in PDB, which form some kind of knotted structures, with simple 3_1 trefoil knots, 4_1, 5_2 Gordian knots, and 6_1 Stevedore knots. Knotted proteins represent a significant challenge to both the experimentalists and theoreticians. Jackson explains when and how the polypeptide chains knot during the folding process with specific examples. Huang and coworkers review the recent progresses in Markov State Models (MSM), which is aimed to bridge the gap between short computer simulations and long observables from optical spectroscopes. These approaches also provide a “coarse-grained picture” of folding pathways as a sequence of transitions among intermediate states, which in some cases can be validated by high-resolution experimental probes. Fang and coworkers study the interaction between proteins and nanoparticles, such as carbon nanotubes, and find proteins can have profound conformational changes upon biding with these potentially toxic nanoparticles. There are many other interesting works in this special issue on the folding phenomena, which help elucidate a clearer picture of the protein folding problem at both microscopic and macroscopic scales. Finally, I would like to thank all the authors for their excellent contributions, as well as the referees for their tremendous effort in helping the present Guest Editor to select these papers and to improve their final quality.....