Current Physical Chemistry - Volume 2, Issue 1, 2012

The present issue marks the beginning of the second year of Current Physical Chemistry (CPC). Although the Journal is still in its infancy, I shall attempt both to draw up a balance of what it has offered so far, as well as to anticipate what it will offer to its readers in the near future and in the long term. In 2011 CPC has published separate feature articles, as well as series of articles grouped together to form a Special Issue concerned with a given topic. In either form of presentation, articles have equally undergone a peer-reviewing process involving at least two external referees, and have discussed experimental and/or theoretical physical chemistry studies of inorganic, organic and biological systems relevant to materials science, metallurgy, electrochemistry, nanotechnologies, medicine and geology. Moreover it has occasionally hosted articles dealing with the historical and philosophical foundations of Physical Chemistry. All the Members of the Editorial Board of CPC are active in various branches of Physical Chemistry, and recent entries now make it composed of scientists originating from all five continents, a combination which ensures a broad coverage of the scope of the Journal both in thematic and territorial terms. Over the past few years, the boundaries of Science (and Physical Chemistry is no exception) have impressively expanded. Such expansion arises not only from the “new” topics which are being studied, but also form the “new” countries (until recently usually referred to as “emerging” countries) where an ever-growing part of research is being carried out. Bentham Science and myself hope that authors from either party will find CPC a suitable forum to record salient phases of an ideal and much profitable challenge, to the benefit of the whole scientific community. As well as an advancement of our understanding of Physical Chemistry, the impressive rise of scientific research (and the attendant rise of competition) have produced a very negative side-effect on the literature - plagiarism- a threat which is the worst of all responses to the old imperative “publish or perish”. I think that plagiarism admits of no mitigation, because with ìt comes something which is even worse than “death” (of research): by setting the clock of scientific progress backwards, it in fact goes counter the “birth” of research. Bentham Science strive to curb this malicious practice by carefully checking the “originality” of each single article submitted prior to considering it for publication in one of their journals, and CPC is no exception. This is one of the essential steps needed to ensure that the quality of the articles published will soon add CPC to the Bentham journals which have already found a seat in the ISI-JCR list and gotten an impact factor, a goal which will prove beneficial to both the authors’ research records and the Journal's reputation. Mentioned in the following list are some new editorial initiatives which Bentham will offer to the readers of CPC. 1. As well as regular articles (either separate, or as part of a Special Issue), the Journal will consider the publication of another kind of contribution (referred to as “Letter to the Editor”), that is, comment articles which offer alternative views/interpretation of issues dealt with by articles previously appeared in CPC. These contributions will undergo the review evaluation by at least one external referee, and the author(s) of the article commented upon will be given the chance to offer an article in response to the comment. 2. The Journal will solicit articles from pre-eminent scientists who have made remarkable contributions to the field of Physical Chemistry. These articles will be published under the heading of a section called “Ground-Breaking Research.”.....

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.....

We review our joint experimental-theoretical effort on the folding of photo-switchable 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. Molecular dynamics simulations reveal a semi-quantitative agreement with the complex response observed in the experiment, allowing one to discuss the process in unprecedented detail. It is found that the nonexponential response is to a large extent introduced by the photo-linker used to initiate folding. Hence, folding of these cross-linked peptides emulates formation of a helical segment in the context of a globular protein rather than folding of an isolated peptide.

The interactions between the nanoscale particles, such as the carbon nanotubes, and biomolecules are essential to the nanoscale particle based biotechnology and biomedical applications, such as gene delivery, cellular imaging, tumor therapy. However, how the structure changes and whether the functions of the biomolecules are affected due to the existence of nanoscale particles are still poorly understood. In this paper, we review some of our recent progresses, which are based on the large scale molecular dynamics simulations, towards this direction. In our studies, by using an all-α domain named HP35 and an all-β domain named YJQ8WW as the examples, we show that the single-walled carbon nanotube (SWCNT), a typical form of hydrophobic nanoscale particle, can considerably change both the secondary and the tertiary structures of the proteins and form the protein-SWCNT complexes, in which the unfolded part of the proteins wrap around the SWCNT. The hydrophobic interaction and π-π stacking interaction between the nanoscale particles and the hydrophobic residues are found to play important roles in our observation.

Many proteins undergo significant structural changes following the hydrolysis of a bound nucleoside triphosphate (NTP) molecule. Davydov has proposed that, in the protein myosin, vibrational excitations are taken advantage of in the energy transduction process following this hydrolysis. Using an atomistic, mixed quantum-classical molecular dynamics model, we have attempted to obtain a more detailed understanding of how this process might take place. Our results indicate that vibrational excitations may be capable of inducing transitions of protein domains from less helical to more helical states. We discuss examples of protein systems for which small changes in ??-helical structure are known to lead to biologically-significant structural effects. Evidence is reviewed supporting a model in which vibrational excitations can lead to utilization of the energy released in NTP hydrolysis through important changes in protein structure following the contraction of a protein α-helix.

α-helix and β-hairpin are the two principal secondary structures in proteins. A large number of experimental and theoretical kinetics and thermodynamics studies of the folding and unfolding of α-helix and β-hairpin structured polypeptides and proteins have been performed. Different theoretical models have been proposed to explain their folding mechanisms. Inconsistencies exist among the various models, which essentially reflect the different understanding of how individual structural elements affect the folding process and stability of protein structures. The present review mainly summarizes our recent simulation studies of the structure stability, folding and unfolding (denaturation) mechanism of various α-helix bundle and β-structure systems.

Fast folding techniques use optical spectroscopic tools to monitor protein folding or unfolding dynamics after a fast triggering such as the laser induced temperature jump. These techniques have greatly improved time resolution of experiments and provide new opportunities for comparison between theory and simulations. However, the direct comparison is still difficult due to two main challenges: a gap between folding relevant timescales (microseconds or above) and length of molecular dynamics simulations (typically tens to hundreds of nanoseconds), and difficulty in directly calculating spectroscopic observables from simulation configurations. This review is focused on recent advances in addressing these two challenges. We describe new methodology that allows simulating folding timescales with an emphasis on Markov State Models. We also review progress on modeling infrared, circular dichroism, and fluorescence spectroscopic signals from protein conformations. At last, we discuss a few studies that directly simulate time-resolved spectroscopy of temperature jump induced unfolding dynamics for a few small proteins. These studies not only provide direct validation of theoretical models, but also greatly improve our understanding of protein folding mechanisms by connecting ensemble averaged spectroscopic observables with atomistic protein conformations.

Since 2000, when they were first identified by Willie Taylor, the number of knotted proteins within the protein database has increased and there are now nearly 300 such structures. The polypeptide chains of these proteins form topologically knotted structures. There are now examples of proteins which form simple 31 trefoil knots, 41, 52 Gordian knots and 61 Stevedore knots. Knotted proteins represent a significant challenge to both the experimental and computational protein folding communities - when and how the polypeptide chains knot during the folding of the proteins poses an additional complexity to the folding landscape. This review describes the experimental and computational studies of the structure, folding and function of naturally occurring knotted proteins including the 31 -trefoil knotted methyltransferases and 52 -knotted ubiquitin C-terminal hydrolases, as well as other systems, in addition to the recently designed trefoil-knotted protein based on the HP0242 dimer.

Bias-Exchange Metadynamics is a powerful technique that can be used for reconstructing the free energy and for enhancing the conformational search in complex biological systems. In this method, a large set of collective variables (CVs) is chosen and several metadynamics simulations are performed on different replicas of the system, each replica biasing a different CV. Exchanges between the bias potentials are periodically attempted according to a replica exchange scheme, and this process is repeated until convergence of the free energy profiles is obtained. Bias-Exchange Metadynamics has been used to understand several different biological phenomena. In particular, due to the efficaciously multidimensional nature of the bias, it is useful to study the folding process of small-to-medium size proteins, and ligandenzyme binding. This review intends to provide a comprehensive description of the algorithm and the approach used to analyze its output. We focus on the practical aspects that need to be addressed when one attempts to apply the method to study protein systems: choice of the appropriate set of parameters and CVs, proper treatment of boundary conditions, convergence criteria, and derivation of a thermodynamic and kinetic model of the system from the simulation results

When one studies protein folding and unfolding by molecular simulations, one faces a great difficulty. Conventional simulations in the canonical ensemble are of little use, because they tend to get trapped in local-minimum-energy states, giving the results in error. A simulation in generalized ensemble performs a random walk in potential energy space and can overcome this difficulty. In this article we review some of powerful generalized-ensemble algorithms, namely, replica-exchange method, simulated tempering, and multicanonical algorithm, and their multidimensional/multivariable extensions.

Intrinsically disordered but biologically active proteins, commonly referred to as IDPs, are readily identified in many biological systems and play critical roles in multiple protein regulatory processes. While disordered in their unbound states, IDPs often, but not always, fold upon binding with their protein interaction partners. Here, we discuss how a class of IDPs directs the targeting, specificity and activity of Protein Phosphatase 1 (PP1). PP1 is major ser/thr phosphatase that plays a critical role in a broad range of biological processes, from muscle contraction to memory formation. In the cell, PP1 is regulated through its interaction with more than 200 regulatory proteins, the majority of which are IDPs. Critically, these PP1:regulatory protein holoenzyme complexes confer specificity to PP1 and are thus the functional forms of the PP1 enzyme in vivo. Furthermore, we discuss the distinct modes of interaction utilized by IDPs to complex with their protein binding partners. We subsequently show, by integrating multiple biophysical tools, that the majority of IDPs that regulate PP1, prefer a conformational selection model.

We present the results of high temperature 500 K Molecular Dynamics simulations of a single-stranded DNA i-motif. The unfolding pathways are compared to a biased metadynamics simulation at 300 K. Our results indicate a remarkable agreement between the trajectories. We found that the unfolding process can be described by two main mechanisms with a small number of eigenvectors.