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Biology ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 6
Author(s):  
Kazuyuki Akasaka ◽  
Akihiro Maeno

Admitting the “Native”, “Unfolded” and “Fibril” states as the three basic generic states of proteins in nature, each of which is characterized with its partial molar volume, here we predict that the interconversion among these generic states N, U, F may be performed simply by making a temporal excursion into the so called “the high-pressure regime”, created artificially by putting the system under sufficiently high hydrostatic pressure, where we convert N to U and F to U, and then back to “the low-pressure regime” (the “Anfinsen regime”), where we convert U back to N (U→N). Provided that the solution conditions (temperature, pH, etc.) remain largely the same, the idea provides a general method for choosing N, U, or F of a protein, to a great extent at will, assisted by the proper use of the external perturbation pressure. A successful experiment is demonstrated for the case of hen lysozyme, for which the amyloid fibril state F prepared at 1 bar is turned almost fully back into its original native state N at 1 bar by going through the “the high-pressure regime”. The outstanding simplicity and effectiveness of pressure in controlling the conformational state of a protein are expected to have a wide variety of applications both in basic and applied bioscience in the future.


2021 ◽  
Author(s):  
Ethan J Walker ◽  
John Q Bettinger ◽  
Kevin A Welle ◽  
Jennifer R Hryhorenko ◽  
Adrian M Molina Vargas ◽  
...  

The oxidation of protein-bound methionines to form methionine sulfoxides has a broad range of biological ramifications, making it important to delineate factors that influence methionine oxidation rates within a protein. This is especially important for biopharmaceuticals, where oxidation can lead to deactivation and degradation. Previously, neighboring residue effects and solvent accessibility (SA) have been shown to impact the susceptibility of methionine residues to oxidation. In this study, we provide proteome-wide evidence that oxidation rates of buried methionine residues are also strongly influenced by the thermodynamic folding stability of proteins. We surveyed the E. coli proteome using several proteomic methodologies and globally measured oxidation rates of methionines in the presence and absence of tertiary structure, as well as folding stabilities of methionine containing domains. The data indicate that buried methionines have a wide range of protection factors against oxidation which correlate strongly with folding stabilities. Concordantly, we show that in comparison to E. coli, the proteome of the thermophile T. thermophilus is significantly more stable and thus more resistant to methionine oxidation. These results indicate that oxidation rates of buried methionines from the native state of proteins can be used as a metric of folding stability. To demonstrate the utility of this correlation, we used native methionine oxidation rates to survey the folding stabilities of E. coli and T. thermophilus proteomes at various temperatures and suggest a model that relates the temperature dependence of the folding stabilities of these two species to their optimal growth temperatures.


2021 ◽  
Vol 104 (6) ◽  
Author(s):  
M. Negri ◽  
G. Tiana ◽  
R. Zecchina
Keyword(s):  

2021 ◽  
Author(s):  
Vojtech Mlynsky ◽  
Michal Janecek ◽  
Petra Kuhrova ◽  
Thorben Frohlking ◽  
Michal Otyepka ◽  
...  

Atomistic molecular dynamics (MD) simulations represent established technique for investigation of RNA structural dynamics. Despite continuous development, contemporary RNA simulations still suffer from suboptimal accuracy of empirical potentials (force fields, ffs) and sampling limitations. Development of efficient enhanced sampling techniques is important for two reasons. First, they allow to overcome the sampling limitations and, second, they can be used to quantify ff imbalances provided they reach a sufficient convergence. Here, we study two RNA tetraloops (TLs), namely the GAGA and UUCG motifs. We perform extensive folding simulations and calculate folding free energies (ΔGfold) with the aim to compare different enhanced sampling techniques and to test several modifications of the nonbonded terms extending the AMBER OL3 RNA ff. We demonstrate that replica exchange solute tempering (REST2) simulations with 12-16 replicas do not show any sign of convergence even when extended to time scale of 120 μs per replica. However, combination of REST2 with well-tempered metadynamics (ST-MetaD) achieves good convergence on a time-scale of 5-10 μs per replica, improving the sampling efficiency by at least two orders of magnitude. Effects of ff modifications on ΔGfold energies were initially explored by the reweighting approach and then validated by new simulations. We tested several manually-prepared variants of gHBfix potential which improve stability of the native state of both TLs by up to ~2 kcal/mol. This is sufficient to conveniently stabilize the folded GAGA TL while the UUCG TL still remains under-stabilized. Appropriate adjustment of van der Waals parameters for C-H...O5' base-phosphate interaction are also shown to be capable of further stabilizing the native states of both TLs by ~0.6 kcal/mol.


Author(s):  
Tatjana Škrbić ◽  
Trinh Xuan Hoang ◽  
Achille Giacometti ◽  
Amos Maritan ◽  
Jayanth R. Banavar

Proteins are the common constituents of all living cells. They are molecular machines that interact with each other as well as with other cell products and carry out a dizzying array of functions with distinction. These interactions follow from their native state structures and therefore understanding sequence-structure relationships is of fundamental importance. What is quite remarkable about proteins is that their understanding necessarily straddles several disciplines. The importance of geometry in defining protein native state structure, the constraints placed on protein behavior by mathematics and physics, the need for proteins to obey the laws of quantum chemistry, and the rich role of evolution and biology all come together in defining protein science. Here we review ideas from the literature and present an interdisciplinary framework that aims to marry ideas from Plato and Darwin and demonstrates an astonishing consilience between disciplines in describing proteins. We discuss the consequences of this framework on protein behavior.


2021 ◽  
Author(s):  
Yulian Gavrilov ◽  
Felix Kümmerer ◽  
Simone Orioli ◽  
Andreas Prestel ◽  
Kresten Lindorff-Larsen ◽  
...  

The conformational heterogeneity of a folded protein can affect both its function but also stability and folding. We recently discovered and characterized a stabilized double mutant (L49I/I57V) of the protein CI2 and showed that state-of-the-art prediction methods could not predict the increased stability relative to the wild-type protein. Here we have examined whether changed native state dynamics, and resulting entropy changes, can explain the stability changes in the double mutant protein, as well as the two single mutant forms. We have combined NMR relaxation measurements of the ps-ns dynamics of amide groups in the backbone and the methyl groups in the side-chains with molecular dynamics simulations to quantify the native state dynamics. The NMR experiments reveal that the mutations have different effects on the conformational flexibility of CI2: A reduction in conformational dynamics (and entropy) of the native state of L49I variant correlates with its decreased stability, while increased dynamics of the I57V and L49I/I57V variants correlates with their increased stability. These findings suggest that explicitly accounting for changes in native state entropy might be needed to improve the predictions of the effect of mutations on protein stability.


Nanomaterials ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 3023
Author(s):  
Marc Rico-Pasto ◽  
Annamaria Zaltron ◽  
Felix Ritort

Single-molecule force spectroscopy has opened a new field of research in molecular biophysics and biochemistry. Pulling experiments on individual proteins permit us to monitor conformational transitions with high temporal resolution and measure their free energy landscape. The force–extension curves of single proteins often present large hysteresis, with unfolding forces that are higher than refolding ones. Therefore, the high energy of the transition state (TS) in these molecules precludes kinetic rates measurements in equilibrium hopping experiments. In irreversible pulling experiments, force-dependent kinetic rates measurements show a systematic discrepancy between the sum of the folding and unfolding TS distances derived by the kinetic Bell–Evans model and the full molecular extension predicted by elastic models. Here, we show that this discrepancy originates from the force-induced movement of TS. Specifically, we investigate the highly kinetically stable protein barnase, using pulling experiments and the Bell–Evans model to characterize the position of its kinetic barrier. Experimental results show that while the TS stays at a roughly constant distance relative to the native state, it shifts with force relative to the unfolded state. Interestingly, a conversion of the protein extension into amino acid units shows that the TS position follows the Leffler–Hammond postulate: the higher the force, the lower the number of unzipped amino acids relative to the native state. The results are compared with the quasi-reversible unfolding–folding of a short DNA hairpin.


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