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Annual Review of Biophysics May 2022The structures and conformational dynamics of proteins, protein complexes, and their noncovalent interactions with other molecules are controlled specifically by the... (Review)
Review
The structures and conformational dynamics of proteins, protein complexes, and their noncovalent interactions with other molecules are controlled specifically by the Gibbs free energy (entropy and enthalpy) of the system. For some organisms, temperature is highly regulated, but the majority of biophysical studies are carried out at room, nonphysiological temperature. In this review, we describe variable-temperature electrospray ionization (vT-ESI) mass spectrometry (MS)-based studies with unparalleled sensitivity, dynamic range, and selectivity for studies of both cold- and heat-induced chemical processes. Such studies provide direct determinations of stabilities, reactivities, and thermodynamic measurements for native and non-native structures of proteins and protein complexes and for protein-ligand interactions. Highlighted in this review are vT-ESI-MS studies that reveal 40 different conformers of chymotrypsin inhibitor 2, a classic two-state (native → unfolded) unfolder, and thermochemistry for a model membrane protein system binding lipid and its regulatory protein.
Topics: Ligands; Protein Folding; Spectrometry, Mass, Electrospray Ionization; Temperature; Thermodynamics
PubMed: 34932911
DOI: 10.1146/annurev-biophys-102221-101121 -
Journal of Chemical Information and... Dec 2023Despite advances in artificial intelligence methods, protein folding remains in many ways an enigma to be solved. Accurate computation of protein folding energetics...
Despite advances in artificial intelligence methods, protein folding remains in many ways an enigma to be solved. Accurate computation of protein folding energetics could help drive fields such as protein and drug design and genetic interpretation. However, the challenge of calculating the state functions governing protein folding from first-principles remains unaddressed. We present here a simple approach that allows us to accurately calculate the energetics of protein folding. It is based on computing the energy of the folded and unfolded states at different temperatures using molecular dynamics simulations. From this, two essential quantities (Δ and ΔCp) are obtained and used to calculate the conformational stability of the protein (Δ). With this approach, we have successfully calculated the energetics of two- and three-state proteins, representatives of the major structural classes, as well as small stability differences (ΔΔ) due to changes in solution conditions or variations in an amino acid residue.
Topics: Molecular Dynamics Simulation; Artificial Intelligence; Thermodynamics; Protein Folding; Proteins
PubMed: 37955428
DOI: 10.1021/acs.jcim.3c01107 -
Current Opinion in Structural Biology Jun 2021Protein structure prediction and design can be regarded as two inverse processes governed by the same folding principle. Although progress remained stagnant over the... (Review)
Review
Protein structure prediction and design can be regarded as two inverse processes governed by the same folding principle. Although progress remained stagnant over the past two decades, the recent application of deep neural networks to spatial constraint prediction and end-to-end model training has significantly improved the accuracy of protein structure prediction, largely solving the problem at the fold level for single-domain proteins. The field of protein design has also witnessed dramatic improvement, where noticeable examples have shown that information stored in neural-network models can be used to advance functional protein design. Thus, incorporation of deep learning techniques into different steps of protein folding and design approaches represents an exciting future direction and should continue to have a transformative impact on both fields.
Topics: Deep Learning; Neural Networks, Computer; Protein Folding; Proteins
PubMed: 33639355
DOI: 10.1016/j.sbi.2021.01.007 -
Protein Science : a Publication of the... Apr 2019Recent progress in de novo protein design has led to an explosion of new protein structures, functions and assemblies. In this essay, I consider how the successes and... (Review)
Review
Recent progress in de novo protein design has led to an explosion of new protein structures, functions and assemblies. In this essay, I consider how the successes and failures in this new area inform our understanding of the proteins in nature and, more generally, the predictive computational modeling of biological systems.
Topics: Animals; Biophysical Phenomena; Humans; Kinetics; Protein Conformation; Protein Folding; Protein Stability; Proteins; Thermodynamics
PubMed: 30746840
DOI: 10.1002/pro.3588 -
Does proteostasis get lost in translation? Implications for protein aggregation across the lifespan.Ageing Research Reviews Sep 2020Protein aggregation is a phenomenon of major relevance in neurodegenerative and neuromuscular disorders, cataracts, diabetes and many other diseases. Research has... (Review)
Review
Protein aggregation is a phenomenon of major relevance in neurodegenerative and neuromuscular disorders, cataracts, diabetes and many other diseases. Research has unveiled that proteins also aggregate in multiple tissues during healthy aging yet, the biological and biomedical relevance of this apparently asymptomatic phenomenon remains to be understood. It is known that proteome homeostasis (proteostasis) is maintained by a balanced protein synthesis rate, high protein synthesis accuracy, efficient protein folding and continual tagging of damaged proteins for degradation, suggesting that protein aggregation during healthy aging may be associated with alterations in both protein synthesis and the proteostasis network (PN) pathways. In particular, dysregulation of protein synthesis and alterations in translation fidelity are hypothesized to lead to the production of misfolded proteins which could explain the occurrence of age-related protein aggregation. Nevertheless, some data on this topic is controversial and the biological mechanisms that lead to widespread protein aggregation remain to be elucidated. We review the recent literature about the age-related decline of proteostasis, highlighting the need to build an integrated view of protein synthesis rate, fidelity and quality control pathways in order to better understand the proteome alterations that occur during aging and in age-related diseases.
Topics: Humans; Longevity; Protein Aggregates; Protein Folding; Proteostasis; Proteostasis Deficiencies
PubMed: 32603841
DOI: 10.1016/j.arr.2020.101119 -
Scientific Reports Feb 2020A hallmark feature of Alzheimer's disease (AD) and other tauopathies is the misfolding, aggregation and cerebral accumulation of tau deposits. Compelling evidence...
A hallmark feature of Alzheimer's disease (AD) and other tauopathies is the misfolding, aggregation and cerebral accumulation of tau deposits. Compelling evidence indicates that misfolded tau aggregates are neurotoxic, producing synaptic loss and neuronal damage. Misfolded tau aggregates are able to spread the pathology from cell-to-cell by a prion like seeding mechanism. The factors implicated in the initiation and progression of tau misfolding and aggregation are largely unclear. In this study, we evaluated the effect of DNA extracted from diverse prokaryotic and eukaryotic cells in tau misfolding and aggregation. Our results show that DNA from various, unrelated gram-positive and gram-negative bacteria results in a more pronounced tau misfolding compared to eukaryotic DNA. Interestingly, a higher effect in promoting tau aggregation was observed for DNA extracted from certain bacterial species previously detected in the brain, CSF or oral cavity of patients with AD. Our findings indicate that microbial DNA may play a previously overlooked role in the propagation of tau protein misfolding and AD pathogenesis, providing a new conceptual framework that positions the compromised blood-brain and intestinal barriers as important sources of microbial DNA in the CNS, opening novel opportunities for therapeutic interventions.
Topics: DNA, Bacterial; DNA, Fungal; Gram-Negative Bacteria; Gram-Positive Bacteria; Polymerization; Protein Folding; tau Proteins
PubMed: 32047247
DOI: 10.1038/s41598-020-59364-x -
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 -
Protein Science : a Publication of the... Nov 2022Intrinsically disordered regions (IDRs) defying the traditional protein structure-function paradigm have been difficult to analyze. The availability of accurate...
Intrinsically disordered regions (IDRs) defying the traditional protein structure-function paradigm have been difficult to analyze. The availability of accurate structure predictions on a large scale in AlphaFoldDB offers a fresh perspective on IDR prediction. Here, we establish three baselines for IDR prediction from AlphaFoldDB models based on the recent CAID dataset. Surprisingly, AlphaFoldDB is highly competitive for predicting both IDRs and conditionally folded binding regions, demonstrating the plasticity of the disorder to structure continuum.
Topics: Protein Conformation; Intrinsically Disordered Proteins; Protein Folding
PubMed: 36210722
DOI: 10.1002/pro.4466 -
Bioinformatics (Oxford, England) Jun 2023Codon usage preference patterns have been associated with modulation of translation efficiency, protein folding, and mRNA decay. However, new studies support that codon...
MOTIVATION
Codon usage preference patterns have been associated with modulation of translation efficiency, protein folding, and mRNA decay. However, new studies support that codon pair usage has also a remarkable effect at the gene expression level. Here, we expand the concept of CAI to answer if codon pair usage patterns can be understood in terms of codon usage bias, or if they offer new information regarding coding translation efficiency.
RESULTS
Through the implementation of a weighting strategy to consider the dicodon contributions, we observe that the dicodon-based measure has greater correlations with gene expression level than CAI. Interestingly, we have noted that dicodons associated with a low value of adaptiveness are related to dicodons which mediate strong translational inhibition in yeast. We have also noticed that some codon-pairs have a smaller dicodon contribution than estimated by the product of the respective codon contributions.
AVAILABILITY AND IMPLEMENTATION
Scripts, implemented in Python, are freely available for download at https://zenodo.org/record/7738276#.ZBIDBtLMIdU.
Topics: Protein Folding; Saccharomyces cerevisiae; Gene Expression
PubMed: 37307098
DOI: 10.1093/bioinformatics/btad380 -
Journal of Molecular Evolution Feb 2023Genetic recombination is a common evolutionary mechanism that produces molecular diversity. However, its consequences on protein folding stability have not attracted the...
Genetic recombination is a common evolutionary mechanism that produces molecular diversity. However, its consequences on protein folding stability have not attracted the same attention as in the case of point mutations. Here, we studied the effects of homologous recombination on the computationally predicted protein folding stability for several protein families, finding less detrimental effects than we previously expected. Although recombination can affect multiple protein sites, we found that the fraction of recombined proteins that are eliminated by negative selection because of insufficient stability is not significantly larger than the corresponding fraction of proteins produced by mutation events. Indeed, although recombination disrupts epistatic interactions, the mean stability of recombinant proteins is not lower than that of their parents. On the other hand, the difference of stability between recombined proteins is amplified with respect to the parents, promoting phenotypic diversity. As a result, at least one third of recombined proteins present stability between those of their parents, and a substantial fraction have higher or lower stability than those of both parents. As expected, we found that parents with similar sequences tend to produce recombined proteins with stability close to that of the parents. Finally, the simulation of protein evolution along the ancestral recombination graph with empirical substitution models commonly used in phylogenetics, which ignore constraints on protein folding stability, showed that recombination favors the decrease of folding stability, supporting the convenience of adopting structurally constrained models when possible for inferences of protein evolutionary histories with recombination.
Topics: Proteins; Protein Folding; Computer Simulation; Phylogeny; Recombination, Genetic; Evolution, Molecular; Protein Stability
PubMed: 36463317
DOI: 10.1007/s00239-022-10080-2