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The Journal of Physical Chemistry. B Oct 2019Cells of the vast majority of organisms are subject to temperature, pressure, pH, ionic strength, and other stresses. We discuss these effects in the light of protein... (Review)
Review
Cells of the vast majority of organisms are subject to temperature, pressure, pH, ionic strength, and other stresses. We discuss these effects in the light of protein folding and protein interactions , in complex environments, in cells, and . Protein phase diagrams provide a way of organizing different structural ensembles that occur under stress and how one can move among ensembles. Experiments that perturb biomolecules or in cells by stressing them have revealed much about the underlying forces that are competing to control protein stability, folding, and function. Two phenomena that emerge and serve to broadly classify effects of the cellular environment are crowding (mainly due to repulsive forces) and sticking (mainly due to attractive forces). The interior of cells is closely balanced between these emergent effects, and stress can tip the balance one way or the other. The free energy scale involved is small but significant on the scale of the "on/off switches" that control signaling in cells or of protein-protein association with a favorable function such as increased enzyme processivity. Quantitative tools from biophysical chemistry will play an important role in elucidating the world of crowding and sticking under stress.
Topics: Animals; Humans; Protein Binding; Protein Folding; Proteins; Stress, Physiological
PubMed: 31386813
DOI: 10.1021/acs.jpcb.9b05467 -
Archives of Biochemistry and Biophysics Jan 2008Confinement and crowding are two major factors that can potentially impact protein folding in cellular environments. Theories based on considerations of excluded volumes... (Review)
Review
Confinement and crowding are two major factors that can potentially impact protein folding in cellular environments. Theories based on considerations of excluded volumes predict disparate effects on protein folding stability for confinement and crowding: confinement can stabilize proteins by over 10k(B)T but crowding has a very modest effect on stability. On the other hand, confinement and crowding are both predicted to favor conformations of the unfolded state which are compact, and consequently may increase the folding rate. These predictions are largely borne out by experimental studies of protein folding under confined and crowded conditions in the test tube. Protein folding in cellular environments is further complicated by interactions with surrounding surfaces and other factors. Concerted theoretical modeling and test-tube and in vivo experiments promise to elucidate the complexity of protein folding in cellular environments.
Topics: Models, Theoretical; Protein Folding; Thermodynamics
PubMed: 17719556
DOI: 10.1016/j.abb.2007.07.013 -
Biomolecules Mar 2020From experimental studies of protein folding, it is now clear that there are two types of folding behavior, i.e., two-state folding and non-two-state folding, and... (Review)
Review
From experimental studies of protein folding, it is now clear that there are two types of folding behavior, i.e., two-state folding and non-two-state folding, and understanding the relationships between these apparently different folding behaviors is essential for fully elucidating the molecular mechanisms of protein folding. This article describes how the presence of the two types of folding behavior has been confirmed experimentally, and discusses the relationships between the two-state and the non-two-state folding reactions, on the basis of available data on the correlations of the folding rate constant with various structure-based properties, which are determined primarily by the backbone topology of proteins. Finally, a two-stage hierarchical model is proposed as a general mechanism of protein folding. In this model, protein folding occurs in a hierarchical manner, reflecting the hierarchy of the native three-dimensional structure, as embodied in the case of non-two-state folding with an accumulation of the molten globule state as a folding intermediate. The two-state folding is thus merely a simplified version of the hierarchical folding caused either by an alteration in the rate-limiting step of folding or by destabilization of the intermediate.
Topics: Circular Dichroism; Kinetics; Protein Conformation; Protein Denaturation; Protein Folding; Proteins
PubMed: 32155758
DOI: 10.3390/biom10030407 -
Scientific Reports Apr 2022Proteins fold in 3-dimensional conformations which are important for their function. Characterizing the global conformation of proteins rigorously and separating...
Proteins fold in 3-dimensional conformations which are important for their function. Characterizing the global conformation of proteins rigorously and separating secondary structure effects from topological effects is a challenge. New developments in applied knot theory allow to characterize the topological characteristics of proteins (knotted or not). By analyzing a small set of two-state and multi-state proteins with no knots or slipknots, our results show that 95.4% of the analyzed proteins have non-trivial topological characteristics, as reflected by the second Vassiliev measure, and that the logarithm of the experimental protein folding rate depends on both the local geometry and the topology of the protein's native state.
Topics: Protein Conformation; Protein Folding; Protein Structure, Secondary; Proteins
PubMed: 35430582
DOI: 10.1038/s41598-022-09924-0 -
Biomolecules Feb 2014While the toxicity of metals and metalloids, like arsenic, cadmium, mercury, lead and chromium, is undisputed, the underlying molecular mechanisms are not entirely... (Review)
Review
While the toxicity of metals and metalloids, like arsenic, cadmium, mercury, lead and chromium, is undisputed, the underlying molecular mechanisms are not entirely clear. General consensus holds that proteins are the prime targets; heavy metals interfere with the physiological activity of specific, particularly susceptible proteins, either by forming a complex with functional side chain groups or by displacing essential metal ions in metalloproteins. Recent studies have revealed an additional mode of metal action targeted at proteins in a non-native state; certain heavy metals and metalloids have been found to inhibit the in vitro refolding of chemically denatured proteins, to interfere with protein folding in vivo and to cause aggregation of nascent proteins in living cells. Apparently, unfolded proteins with motile backbone and side chains are considerably more prone to engage in stable, pluridentate metal complexes than native proteins with their well-defined 3D structure. By interfering with the folding process, heavy metal ions and metalloids profoundly affect protein homeostasis and cell viability. This review describes how heavy metals impede protein folding and promote protein aggregation, how cells regulate quality control systems to protect themselves from metal toxicity and how metals might contribute to protein misfolding disorders.
Topics: Animals; Humans; Metalloids; Metals, Heavy; Protein Aggregates; Protein Folding; Proteins
PubMed: 24970215
DOI: 10.3390/biom4010252 -
EMBO Reports Feb 2022Protein folding is a fundamental process of life with important implications throughout biology. Indeed, tens of thousands of mutations have been associated with... (Review)
Review
Protein folding is a fundamental process of life with important implications throughout biology. Indeed, tens of thousands of mutations have been associated with diseases, and most of these mutations are believed to affect protein folding rather than function. Correct folding is also a key element of design. These factors have motivated decades of research on protein folding. Unfortunately, knowledge of membrane protein folding lags that of soluble proteins. This gap is partly caused by the greater technical challenges associated with membrane protein studies, but also because of additional complexities. While soluble proteins fold in a homogenous water environment, membrane proteins fold in a setting that ranges from bulk water to highly charged to apolar. Thus, the forces that drive folding vary in different regions of the protein, and this complexity needs to be incorporated into our understanding of the folding process. Here, we review our understanding of membrane protein folding biophysics. Despite the greater challenge, better model systems and new experimental techniques are starting to unravel the forces and pathways in membrane protein folding.
Topics: Membrane Proteins; Protein Folding
PubMed: 35133709
DOI: 10.15252/embr.202153025 -
Science Advances May 2018Precise protein folding is essential for the survival of all cells, and protein misfolding causes a number of diseases that lack effective therapies, yet the general...
Precise protein folding is essential for the survival of all cells, and protein misfolding causes a number of diseases that lack effective therapies, yet the general principles governing protein folding in the cell remain poorly understood. In vivo, folding can begin cotranslationally and protein quality control at the ribosome is essential for cellular proteostasis. We directly characterize and compare the refolding and cotranslational folding trajectories of the protein HaloTag. We introduce new techniques for both measuring folding kinetics and detecting the conformations of partially folded intermediates during translation in real time. We find that, although translation does not affect the rate-limiting step of HaloTag folding, a key aggregation-prone intermediate observed during in vitro refolding experiments is no longer detectable. This rerouting of the folding pathway increases HaloTag's folding efficiency and may serve as a general chaperone-independent mechanism of quality control by the ribosome.
Topics: Kinetics; Models, Molecular; Protein Conformation; Protein Folding; Protein Refolding; Proteins
PubMed: 29854950
DOI: 10.1126/sciadv.aas9098 -
International Journal of Molecular... Feb 2009The large surface area and small size of nanoparticles provide properties and applications that are distinct from those of bulk materials. The ability of nanoparticles... (Review)
Review
The large surface area and small size of nanoparticles provide properties and applications that are distinct from those of bulk materials. The ability of nanoparticles to influence protein folding and aggregation is interesting, not only because of the potential beneficial applications, but also the potential risks to human health and the environment. This makes it essential that we understand the effect of nanoparticles on fundamental biological process, like protein folding. Here, we review studies that have examined the effect of nanoparticles on protein folding and aggregation, providing insight both into the mechanisms of these processes and how they may be controlled.
Topics: Absorption; Amyloid; Nanoparticles; Protein Folding
PubMed: 19333426
DOI: 10.3390/ijms10020646 -
PloS One May 2007Calculation of the free energy of protein folding and delineation of its pre-organization are of foremost importance for understanding, predicting and designing...
Calculation of the free energy of protein folding and delineation of its pre-organization are of foremost importance for understanding, predicting and designing biological macromolecules. Here, we introduce an energy smoothing variant of parallel tempering replica exchange Monte Carlo (REMS) that allows for efficient configurational sampling of flexible solutes under the conditions of molecular hydration. Its usage to calculate the thermal stability of a model globular protein, Trp cage TC5b, achieves excellent agreement with experimental measurements. We find that the stability of TC5b is attained through the coupled formation of local and non-local interactions. Remarkably, many of these structures persist at high temperature, concomitant with the origin of native-like configurations and mesostates in an otherwise macroscopically disordered unfolded state. Graph manifold learning reveals that the conversion of these mesostates to the native state is structurally heterogeneous, and that the cooperativity of their formation is encoded largely by the unfolded state ensemble. In all, these studies establish the extent of thermodynamic and structural pre-organization of folding of this model globular protein, and achieve the calculation of macromolecular stability ab initio, as required for ab initio structure prediction, genome annotation, and drug design.
Topics: Protein Conformation; Protein Folding; Proteins
PubMed: 17505540
DOI: 10.1371/journal.pone.0000446 -
Molecules (Basel, Switzerland) May 2022Protein folding is a complicated phenomenon including various time scales (μs to several s), and various structural indices are required to analyze it. The... (Review)
Review
Protein folding is a complicated phenomenon including various time scales (μs to several s), and various structural indices are required to analyze it. The methodologies used to study this phenomenon also have a wide variety and employ various experimental and computational techniques. Thus, a simple speculation does not serve to understand the folding mechanism of a protein. In the present review, we discuss the recent studies conducted by the author and their colleagues to decode amino acid sequences to obtain information on protein folding. We investigate globin-like proteins, ferredoxin-like fold proteins, IgG-like beta-sandwich fold proteins, lysozyme-like fold proteins and β-trefoil-like fold proteins. Our techniques are based on statistics relating to the inter-residue average distance, and our studies performed so far indicate that the information obtained from these analyses includes data on the protein folding mechanism. The relationships between our results and the actual protein folding phenomena are also discussed.
Topics: Amino Acid Sequence; Models, Molecular; Protein Folding; Proteins; Staphylococcal Protein A
PubMed: 35566370
DOI: 10.3390/molecules27093020