-
Biomolecules Apr 2022Protein folding and structural biology are highly active disciplines that combine basic research in various fields, including biology, chemistry, physics, and computer...
Protein folding and structural biology are highly active disciplines that combine basic research in various fields, including biology, chemistry, physics, and computer science, with practical applications in biomedicine and nanotechnology. However, there are still gaps in the understanding of the detailed mechanisms of protein folding, and protein structure-function relations. In an effort to bridge these gaps, this paper studies the equivalence of proteins and origami. Research on proteins and origami provides strong evidence to support the use of origami folding principles and mechanical models to explain aspects of proteins formation and function. Although not identical, the equivalence of origami and proteins emerges in: (i) the folding processes, (ii) the shape and structure of proteins and origami models, and (iii) the intrinsic mechanical properties of the folded structures/models, which allows them to synchronically fold/unfold and effectively distribute forces to the whole structure. As a result, origami can contribute to the understanding of various key protein-related mechanisms and support the design of de novo proteins and nanomaterials.
Topics: Nanostructures; Nanotechnology; Protein Folding; Proteins
PubMed: 35625549
DOI: 10.3390/biom12050622 -
Molecules (Basel, Switzerland) Jul 2022Despite the recent advances in the prediction of protein structures by deep neutral networks, the elucidation of protein-folding mechanisms remains challenging. A... (Review)
Review
Despite the recent advances in the prediction of protein structures by deep neutral networks, the elucidation of protein-folding mechanisms remains challenging. A promising theory for describing protein folding is a coarse-grained statistical mechanical model called the Wako-Saitô-Muñoz-Eaton (WSME) model. The model can calculate the free-energy landscapes of proteins based on a three-dimensional structure with low computational complexity, thereby providing a comprehensive understanding of the folding pathways and the structure and stability of the intermediates and transition states involved in the folding reaction. In this review, we summarize previous and recent studies on protein folding and dynamics performed using the WSME model and discuss future challenges and prospects. The WSME model successfully predicted the folding mechanisms of small single-domain proteins and the effects of amino-acid substitutions on protein stability and folding in a manner that was consistent with experimental results. Furthermore, extended versions of the WSME model were applied to predict the folding mechanisms of multi-domain proteins and the conformational changes associated with protein function. Thus, the WSME model may contribute significantly to solving the protein-folding problem and is expected to be useful for predicting protein folding, stability, and dynamics in basic research and in industrial and medical applications.
Topics: Kinetics; Models, Molecular; Protein Folding; Protein Stability; Proteins; Thermodynamics
PubMed: 35889332
DOI: 10.3390/molecules27144460 -
International Journal of Molecular... Mar 2023We review the key steps leading to an improved analysis of thermal protein unfolding. Thermal unfolding is a dynamic cooperative process with many short-lived... (Review)
Review
We review the key steps leading to an improved analysis of thermal protein unfolding. Thermal unfolding is a dynamic cooperative process with many short-lived intermediates. Protein unfolding has been measured by various spectroscopic techniques that reveal structural changes, and by differential scanning calorimetry (DSC) that provides the heat capacity change C(T). The corresponding temperature profiles of enthalpy ΔH(T), entropy ΔS(T), and free energy ΔG(T) have thus far been evaluated using a chemical equilibrium two-state model. Taking a different approach, we demonstrated that the temperature profiles of enthalpy ΔH(T), entropy ΔS(T), and free energy ΔG(T) can be obtained directly by a numerical integration of the heat capacity profile C(T). DSC thus offers the unique possibility to assess these parameters without resorting to a model. These experimental parameters now allow us to examine the predictions of different unfolding models. The standard two-state model fits the experimental heat capacity peak quite well. However, neither the enthalpy nor entropy profiles (predicted to be almost linear) are congruent with the measured sigmoidal temperature profiles, nor is the parabolic free energy profile congruent with the experimentally observed trapezoidal temperature profile. We introduce three new models, an empirical two-state model, a statistical-mechanical two-state model and a cooperative statistical-mechanical multistate model. The empirical model partially corrects for the deficits of the standard model. However, only the two statistical-mechanical models are thermodynamically consistent. The two-state models yield good fits for the enthalpy, entropy and free energy of unfolding of small proteins. The cooperative statistical-mechanical multistate model yields perfect fits, even for the unfolding of large proteins such as antibodies.
Topics: Protein Denaturation; Thermodynamics; Protein Unfolding; Entropy; Proteins; Calorimetry, Differential Scanning; Protein Folding
PubMed: 36982534
DOI: 10.3390/ijms24065457 -
Quarterly Reviews of Biophysics Nov 2007Two fundamentally different views of how proteins fold are now being debated. Do proteins fold through multiple unpredictable routes directed only by the energetically... (Review)
Review
Two fundamentally different views of how proteins fold are now being debated. Do proteins fold through multiple unpredictable routes directed only by the energetically downhill nature of the folding landscape or do they fold through specific intermediates in a defined pathway that systematically puts predetermined pieces of the target native protein into place? It has now become possible to determine the structure of protein folding intermediates, evaluate their equilibrium and kinetic parameters, and establish their pathway relationships. Results obtained for many proteins have serendipitously revealed a new dimension of protein structure. Cooperative structural units of the native protein, called foldons, unfold and refold repeatedly even under native conditions. Much evidence obtained by hydrogen exchange and other methods now indicates that cooperative foldon units and not individual amino acids account for the unit steps in protein folding pathways. The formation of foldons and their ordered pathway assembly systematically puts native-like foldon building blocks into place, guided by a sequential stabilization mechanism in which prior native-like structure templates the formation of incoming foldons with complementary structure. Thus the same propensities and interactions that specify the final native state, encoded in the amino-acid sequence of every protein, determine the pathway for getting there. Experimental observations that have been interpreted differently, in terms of multiple independent pathways, appear to be due to chance misfolding errors that cause different population fractions to block at different pathway points, populate different pathway intermediates, and fold at different rates. This paper summarizes the experimental basis for these three determining principles and their consequences. Cooperative native-like foldon units and the sequential stabilization process together generate predetermined stepwise pathways. Optional misfolding errors are responsible for 3-state and heterogeneous kinetic folding.
Topics: Models, Molecular; Protein Folding; Proteins
PubMed: 18405419
DOI: 10.1017/S0033583508004654 -
Proceedings of the National Academy of... Aug 2022Repeat proteins are made with tandem copies of similar amino acid stretches that fold into elongated architectures. These proteins constitute excellent model systems to...
Repeat proteins are made with tandem copies of similar amino acid stretches that fold into elongated architectures. These proteins constitute excellent model systems to investigate how evolution relates to structure, folding, and function. Here, we propose a scheme to map evolutionary information at the sequence level to a coarse-grained model for repeat-protein folding and use it to investigate the folding of thousands of repeat proteins. We model the energetics by a combination of an inverse Potts-model scheme with an explicit mechanistic model of duplications and deletions of repeats to calculate the evolutionary parameters of the system at the single-residue level. These parameters are used to inform an Ising-like model that allows for the generation of folding curves, apparent domain emergence, and occupation of intermediate states that are highly compatible with experimental data in specific case studies. We analyzed the folding of thousands of natural Ankyrin repeat proteins and found that a multiplicity of folding mechanisms are possible. Fully cooperative all-or-none transitions are obtained for arrays with enough sequence-similar elements and strong interactions between them, while noncooperative element-by-element intermittent folding arose if the elements are dissimilar and the interactions between them are energetically weak. Additionally, we characterized nucleation-propagation and multidomain folding mechanisms. We show that the global stability and cooperativity of the repeating arrays can be predicted from simple sequence scores.
Topics: Ankyrin Repeat; Models, Chemical; Protein Folding
PubMed: 35905321
DOI: 10.1073/pnas.2204131119 -
Aging Apr 2018
Topics: Animals; Humans; Protein Folding; Protein Transport
PubMed: 29706613
DOI: 10.18632/aging.101435 -
ACS Chemical Biology Jun 2018Since the proposal of Anfinsen's thermodynamic hypothesis in 1963, our understanding of protein folding and dynamics has gained significant appreciation of its nuance... (Review)
Review
Since the proposal of Anfinsen's thermodynamic hypothesis in 1963, our understanding of protein folding and dynamics has gained significant appreciation of its nuance and complexity. Intrinsically disordered proteins, chameleonic sequences, morpheeins, and metamorphic proteins have broadened the protein folding paradigm. Here, we discuss noncanonical protein folding patterns, with an emphasis on metamorphic proteins, and we review known metamorphic proteins that occur naturally and that have been engineered in the laboratory. Finally, we discuss research areas surrounding metamorphic proteins that are primed for future exploration, including evolution, drug discovery, and the quest for previously unrecognized metamorphs. As we enter an age where we are capable of complex bioinformatic searches and de novo protein design, we are primed to search for previously unrecognized metamorphic proteins and to design our own metamorphs to act as targeted, switchable drugs; biosensors; and more.
Topics: Animals; Bacteria; Humans; Intrinsically Disordered Proteins; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Engineering; Protein Folding; Protein Unfolding
PubMed: 29787234
DOI: 10.1021/acschembio.8b00276 -
Current Opinion in Structural Biology Feb 2022Delineating the folding steps of helical-bundle membrane proteins has been a challenging task. Many questions remain unanswered, including the conformation and stability... (Review)
Review
Delineating the folding steps of helical-bundle membrane proteins has been a challenging task. Many questions remain unanswered, including the conformation and stability of the states populated during folding, the shape of the energy barriers between the states, and the role of lipids as a solvent in mediating the folding. Recently, theoretical frames have matured to a point that permits detailed dissection of the folding steps, and advances in experimental techniques at both single-molecule and ensemble levels enable selective modulation of specific steps for quantitative determination of the folding energy landscapes. We also discuss how lipid molecules would play an active role in shaping the folding energy landscape of membrane proteins, and how folding of multi-domain membrane proteins can be understood based on our current knowledge. We conclude this review by offering an outlook for emerging questions in the study of membrane protein folding.
Topics: Membrane Proteins; Protein Folding; Thermodynamics
PubMed: 34995926
DOI: 10.1016/j.sbi.2021.11.013 -
Essays in Biochemistry Dec 2022How do proteins interact in the cellular environment? Which interactions stabilize liquid-liquid phase separated condensates? Are the concepts, which have been developed...
How do proteins interact in the cellular environment? Which interactions stabilize liquid-liquid phase separated condensates? Are the concepts, which have been developed for specific protein complexes also applicable to higher-order assemblies? Recent discoveries prompt for a universal framework for protein interactions, which can be applied across the scales of protein communities. Here, we discuss how our views on protein interactions have evolved from rigid structures to conformational ensembles of proteins and discuss the open problems, in particular related to biomolecular condensates. Protein interactions have evolved to follow changes in the cellular environment, which manifests in multiple modes of interactions between the same partners. Such cellular context-dependence requires multiplicity of binding modes (MBM) by sampling multiple minima of the interaction energy landscape. We demonstrate that the energy landscape framework of protein folding can be applied to explain this phenomenon, opening a perspective toward a physics-based, universal model for cellular protein behaviors.
Topics: Proteins; Protein Folding
PubMed: 36416856
DOI: 10.1042/EBC20220044 -
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