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Journal of Molecular Biology Oct 2023The study of protein folding plays a crucial role in improving our understanding of protein function and of the relationship between genetics and phenotypes. In...
The study of protein folding plays a crucial role in improving our understanding of protein function and of the relationship between genetics and phenotypes. In particular, understanding the thermodynamics and kinetics of the folding process is important for uncovering the mechanisms behind human disorders caused by protein misfolding. To address this issue, it is essential to collect and curate experimental kinetic and thermodynamic data on protein folding. K-Pro is a new database designed for collecting and storing experimental kinetic data on monomeric proteins, with a two-state folding mechanism. With 1,529 records from 62 proteins corresponding to 65 structures, K-Pro contains various kinetic parameters such as the logarithm of the folding and unfolding rates, Tanford's β and the ϕ values. When available, the database also includes thermodynamic parameters associated with the kinetic data. K-Pro features a user-friendly interface that allows browsing and downloading kinetic data of interest. The graphical interface provides a visual representation of the protein and mutants, and it is cross-linked to key databases such as PDB, UniProt, and PubMed. K-Pro is open and freely accessible through https://folding.biofold.org/k-pro and supports the latest versions of popular browsers.
Topics: Humans; Databases, Protein; Kinetics; Protein Denaturation; Protein Folding; Proteins; Thermodynamics; Mutant Proteins
PubMed: 37625584
DOI: 10.1016/j.jmb.2023.168245 -
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 -
ACS Nano Jul 2017Single-molecule studies of protein folding hold keys to unveiling protein folding pathways and elusive intermediate folding states-attractive pharmaceutical targets....
Single-molecule studies of protein folding hold keys to unveiling protein folding pathways and elusive intermediate folding states-attractive pharmaceutical targets. Although conventional single-molecule approaches can detect folding intermediates, they presently lack throughput and require elaborate labeling. Here, we theoretically show that measurements of ionic current through a nanopore containing a protein can report on the protein's folding state. Our all-atom molecular dynamics (MD) simulations show that the unfolding of a protein lowers the nanopore ionic current, an effect that originates from the reduction of ion mobility in proximity to a protein. Using a theoretical model, we show that the average change in ionic current produced by a folding-unfolding transition is detectable despite the orientational and conformational heterogeneity of the folded and unfolded states. By analyzing millisecond-long all-atom MD simulations of multiple protein transitions, we show that a nanopore ionic current recording can detect folding-unfolding transitions in real time and report on the structure of folding intermediates.
Topics: Databases, Protein; Ion Transport; Molecular Dynamics Simulation; Nanopores; Protein Conformation; Protein Folding; Protein Unfolding; Proteins
PubMed: 28693322
DOI: 10.1021/acsnano.7b02718 -
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 -
Methods in Molecular Biology (Clifton,... 2022Computational coarse-grained models play a fundamental role as a research tool in protein folding, and they are important in bridging theory and experiments. Folding...
Computational coarse-grained models play a fundamental role as a research tool in protein folding, and they are important in bridging theory and experiments. Folding mechanisms are generally discussed using the energy landscape framework, which is well mapped within a class of simplified structure-based models. In this chapter, simplified computer models are discussed with special focus on structure-based ones.
Topics: Computer Simulation; Molecular Dynamics Simulation; Protein Folding; Thermodynamics
PubMed: 34845616
DOI: 10.1007/978-1-0716-1716-8_16 -
Journal of Chemical Theory and... Mar 2022Constantly advancing computer simulations of biomolecules provide huge amounts of data that are difficult to interpret. In particular, obtaining insights into functional...
Constantly advancing computer simulations of biomolecules provide huge amounts of data that are difficult to interpret. In particular, obtaining insights into functional aspects of macromolecular dynamics, often related to cascades of transient events, calls for methodologies that depart from the well-grounded framework of equilibrium statistical physics. One of the approaches toward the analysis of complex temporal data which has found applications in the fields of neuroscience and econometrics is Granger causality analysis. It allows determining which components of multidimensional time series are most influential for the evolution of the entire system, thus providing insights into causal relations within the dynamic structure of interest. In this work, we apply Granger analysis to a long molecular dynamics trajectory depicting repetitive folding and unfolding of a mini β-hairpin protein, CLN025. We find objective, quantitative evidence indicating that rearrangements within the hairpin turn region are determinant for protein folding and unfolding. On the contrary, interactions between hairpin arms score low on the causality scale. Taken together, these findings clearly favor the concept of zipperlike folding, which is one of two postulated β-hairpin folding mechanisms. More importantly, the results demonstrate the possibility of a conclusive application of Granger causality analysis to a biomolecular system.
Topics: Molecular Dynamics Simulation; Oligopeptides; Protein Folding
PubMed: 35167755
DOI: 10.1021/acs.jctc.1c00945 -
Current Opinion in Structural Biology Feb 2021Protein folding in vivo has been largely understood in the context of molecular chaperones preventing aggregation of nascent polypeptides in the crowded cellular... (Review)
Review
Protein folding in vivo has been largely understood in the context of molecular chaperones preventing aggregation of nascent polypeptides in the crowded cellular environment. Nascent chains utilize the crowded environment in favor of productive folding by direct physical connection with cellular macromolecules. The intermolecular repulsive forces by large excluded volume and surface charges of interacting cellular macromolecules, exerting 'social distancing' measure among folding intermediates, could play an important role in stabilizing their physically connected polypeptides against aggregation regardless of the physical connection types. The generic intrinsic chaperone activity of cellular macromolecules likely provides a robust cellular environment for the productive protein folding and solubility maintenance at the whole proteome level.
Topics: Macromolecular Substances; Molecular Chaperones; Physical Distancing; Protein Folding; Proteome
PubMed: 33238232
DOI: 10.1016/j.sbi.2020.10.014 -
Physical Biology Jul 2018Proteins must fold and function in the immensely complex environment of a cell, i.e. the cytoplasm-this is far from the ideal test-tube setting of a dilute solution.... (Review)
Review
Proteins must fold and function in the immensely complex environment of a cell, i.e. the cytoplasm-this is far from the ideal test-tube setting of a dilute solution. Here we review the advances in protein folding and dynamics inside the cell. In developing principles of protein behavior in vivo, we also begin to understand the organization and dynamics of the cytoplasm, unifying the single protein scale with the many-protein architectures at the subcellular scale. Our group has significantly contributed to this frontier by characterizing the effect of macromolecular crowding on the distribution of protein conformations. Additionally, we provide a personal perspective on becoming a theoretical biological physicist in the era of interdisciplinary research that has been greatly influenced by Dr Kamal Shukla. We also share our view on the future direction of protein folding inside a cell.
Topics: Macromolecular Substances; Protein Conformation; Protein Folding
PubMed: 29939151
DOI: 10.1088/1478-3975/aaced2 -
Advances in Experimental Medicine and... 2017Stress and misfolded proteins result to dysfunction in the cell, often leading to neurodegenerative diseases and aging. Misfolded proteins form toxic aggregates that... (Review)
Review
Stress and misfolded proteins result to dysfunction in the cell, often leading to neurodegenerative diseases and aging. Misfolded proteins form toxic aggregates that threaten cell's stability and normal functions. In order to restore its homeostasis, the cell activates the UPR system. Leading role in the restoration play the molecular chaperones which target the misfolded proteins with the purpose of either helping them to unfold and refold to their natural state or lead them degradation. This paper aims to present some of the most known molecular chaperones and their relation with diseases associated to protein misfolding and neurodegeneration, as well as the role of chaperones in proteostasis.
Topics: Endoplasmic Reticulum Stress; Humans; Molecular Chaperones; Neurodegenerative Diseases; Protein Folding; Protein Unfolding; Proteolysis; Unfolded Protein Response
PubMed: 28971461
DOI: 10.1007/978-3-319-57379-3_20 -
Journal of Chemical Information and... Apr 2023Recent advances in machine learning methods have had a significant impact on protein structure prediction, but accurate generation and characterization of...
Recent advances in machine learning methods have had a significant impact on protein structure prediction, but accurate generation and characterization of protein-folding pathways remains intractable. Here, we demonstrate how protein folding trajectories can be generated using a directed walk strategy operating in the space defined by the residue-level contact-map. This double-ended strategy views protein folding as a series of discrete transitions between connected minima on the potential energy surface. Subsequent reaction-path analysis for each transition enables thermodynamic and kinetic characterization of each protein-folding path. We validate the protein-folding paths generated by our discretized-walk strategy against direct molecular dynamics simulations for a series of model coarse-grained proteins constructed from hydrophobic and polar residues. This comparison demonstrates that ranking discretized paths based on the intermediate energy barriers provides a convenient route to identifying physically sensible folding ensembles. Importantly, by using directed walks in the protein contact-map space, we circumvent several of the traditional challenges associated with protein-folding studies, namely, long time scales required and the choice of a specific order parameter to drive the folding process. As such, our approach offers a useful new route for studying the protein-folding problem.
Topics: Proteins; Protein Folding; Molecular Dynamics Simulation; Thermodynamics; Hydrophobic and Hydrophilic Interactions; Protein Conformation
PubMed: 36995250
DOI: 10.1021/acs.jcim.3c00023