Many large proteins suffer from slow or inefficient folding in vitro. It has long been known that this problem can be alleviated in vivo if proteins start folding cotranslationally. However, the molecular mechanisms underlying this improvement have not been well established. To address this question, we use an all-atom simulation-based algorithm to compute the folding properties of various large protein domains as a function of nascent chain length. We find that for certain proteins, there exists a narrow window of lengths that confers both thermodynamic stability and fast folding kinetics. Beyond these lengths, folding is drastically slowed by nonnative interactions involving C-terminal residues. Thus, cotranslational folding is predicted to be beneficial because it allows proteins to take advantage of this optimal window of lengths and thus avoid kinetic traps. Interestingly, many of these proteins’ sequences contain conserved rare codons that may slow down synthesis at this optimal window, suggesting that synthesis rates may be evolutionarily tuned to optimize folding. Using kinetic modeling, we show that under certain conditions, such a slowdown indeed improves cotranslational folding efficiency by giving these nascent chains more time to fold. In contrast, other proteins are predicted not to benefit from cotranslational folding due to a lack of significant nonnative interactions, and indeed these proteins’ sequences lack conserved C-terminal rare codons. Together, these results shed light on the factors that promote proper protein folding in the cell and how biomolecular self-assembly may be optimized evolutionarily.
Impairment in autonomic self-regulatory functioning reflected by reduced heart rate variability (HRV) is a common feature of alcohol use disorder (AUD) and is believed to heighten AUD relapse risk. However, to date, no study has explored associations between in natura HRV and subsequent alcohol use among individuals seeking AUD recovery. In this study, 42 adults in the first year of a current AUD recovery attempt were monitored for 4 days using ambulatory electrocardiogram, followed by 90 days of alcohol use monitoring using timeline follow-back. HRV indices (independent variables) reflecting autonomic neurocardiac engagement were calculated from electrocardiogram recordings. Alcohol use (dependent variable) was calculated from timeline follow-back and expressed as per cent days abstinent (PDA). The sample was 73.81% White/European American, 19.05% Black/African American, 4.76% Asian, and 2.38% Other race/Mixed race. As predicted, higher parasympathetically mediated HRV and lower heart rate were associated with greater PDA over 90-day follow-up. Additionally, interactions between these measures and baseline PDA indicated higher parasympathetically mediated HRV and lower heart rate mitigated the deleterious positive association between baseline and follow-up alcohol use. Including factors known to influence alcohol use and/or HRV in the models did not meaningfully alter their results. Findings are consistent with psychophysiological theories implicating autonomic self-regulatory functioning in AUD treatment outcomes and suggest that select HRV indices may have utility as indicants of risk for alcohol use lapse in individuals in early AUD recovery. Findings provide theoretical support for HRV Biofeedback for this population, which exercises the psychophysiological systems that support self-regulation.
Many large proteins suffer from slow or inefficient folding in vitro.Here, we provide evidence that this problem can be alleviated in vivo if proteins start folding co-translationally. Using an all-atom simulation-based algorithm, we compute the folding properties of various large protein domains as a function of nascent chain length, and find that for certain proteins, there exists a narrow window of lengths that confers both thermodynamic stability and fast folding kinetics. Beyond these lengths, folding is drastically slowed by non-native interactions involving C-terminal residues. Thus, cotranslational folding is predicted to be beneficial because it allows proteins to take advantage of this optimal window of lengths and thus avoid kinetic traps. Interestingly, many of these proteins' sequences contain conserved rare codons that may slow down synthesis at this optimal window, suggesting that synthesis rates may be evolutionarily tuned to optimize folding. Using kinetic modelling, we show that under certain conditions, such a slowdown indeed improves co-translational folding efficiency by giving these nascent chains more time to fold. In contrast, other proteins are predicted not to benefit from co-translational folding due to a lack of significant non-native interactions, and indeed these proteins' sequences lack conserved C-terminal rare codons. Together, these results shed light on the factors that promote proper protein folding in the cell, and how biomolecular self-assembly may be optimized evolutionarily.
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