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Solving the protein folding problem….
FEBS Lett
December 2024
Department of Biological Sciences, Munster Technological University, Cork, Ireland.
The protein folding problem was, to paraphrase Churchill, 'A riddle wrapped in a mystery inside an enigma'. The riddle, in this context, was the folding code; what interactions at the amino acid level are driving the folding process? The mystery was the kinetic question (Levinthal's paradox); how does the folding process occur so quickly (typically in timescales ranging from μS to mS)? Finally, the enigma represents the computational problem of developing approaches to predict the final folded sate of a protein given only its amino acid sequence. Herein, I trace the path to solving this riddle wrapped in a mystery inside an enigma.
View Article and Find Full Text PDFProtein folding rate evolution upon mutations.
Biophys Rev
August 2023
IMASL-CONICET, Universidad Nacional de San Luis, Ejército de Los Andes 950, 5700 San Luis, Argentina.
Despite the spectacular success of cutting-edge protein fold prediction methods, many critical questions remain unanswered, including why proteins can reach their native state in a biologically reasonable time. A satisfactory answer to this simple question could shed light on the slowest folding rate of proteins as well as how mutations-amino-acid substitutions and/or post-translational modifications-might affect it. Preliminary results indicate that (i) Anfinsen's dogma validity ensures that proteins reach their native state on a reasonable timescale regardless of their sequence or length, and (ii) it is feasible to determine the evolution of protein folding rates without accounting for epistasis effects or the mutational trajectories between the starting and target sequences.
View Article and Find Full Text PDFProtein folding - seeing is deceiving.
Protein Sci
August 2021
T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, Maryland, USA.
This Perspective is intended to raise questions about the conventional interpretation of protein folding. According to the conventional interpretation, developed over many decades, a protein population can visit a vast number of conformations under unfolding conditions, but a single dominant native population emerges under folding conditions. Accordingly, folding comes with a substantial loss of conformational entropy.
View Article and Find Full Text PDFSolution of Levinthal's Paradox and a Physical Theory of Protein Folding Times.
Biomolecules
February 2020
Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia.
"How do proteins fold?" Researchers have been studying different aspects of this question for more than 50 years. The most conceptual aspect of the problem is how protein can find the global free energy minimum in a biologically reasonable time, without exhaustive enumeration of all possible conformations, the so-called "Levinthal's paradox." Less conceptual but still critical are aspects about factors defining folding times of particular proteins and about perspectives of machine learning for their prediction.
View Article and Find Full Text PDFManagement of cyclic vomiting syndrome in adults: Evidence review.
Neurogastroenterol Motil
June 2019
Division of Gastroenterology, Department of Medicine, University of Minnesota, Minneapolis Veterans Affairs Healthcare System, Minneapolis, Minnesota.
Background: This evidence review was conducted to inform the accompanying clinical practice guideline on the management of cyclic vomiting syndrome (CVS) in adults.
Methods: We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and focused on interventions aimed at prophylactic management and abortive treatment of adults with CVS. Specifically, this evidence review addresses the following clinical questions: (a) Should the following pharmacologic agents be used for prophylaxis of CVS: amitriptyline, topiramate, aprepitant, zonisamide/levetiracetam, or mitochondrial supplements? (b) Should the following pharmacologic agents be used for abortive treatment: triptans or aprepitant?
Results: We found very low-quality evidence to support the use of the following agents for prophylactic and abortive treatment of CVS: amitriptyline, topiramate, aprepitant, zonisamide/levetiracetam, and mitochondrial supplements.
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