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Protein Folding

Author(s):
Publication Date:
May 8, 2024
Copyright © 2024 American Chemical Society
eISBN:
‍9780841296381
DOI:
10.1021/acsinfocus.7e7032
Read Time:
four to five hours
Collection:
3
Publisher:
American Chemical Society
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Life as we know it would not exist if proteins did not fold into functional three-dimensional structures, where α-helices, loops, and β-sheets act together to form active sites that drive a myriad of biochemical reactions in the cell. The failure of this process is linked to the pathology of various diseases, such as neurodegenerative disorders like Alzheimer’s, genetic conditions (like cystic fibrosis), and cancer. It is no wonder that close to $2 billion in worldwide research funding has been devoted over the last five years (2019–2025) to helping scientists understand the molecular details of protein folding, how it can fail in ways that promote disease in humans, and clinical paths to treat or prevent diseases linked to protein misfolding.

 

This primer is prerequisite reading to the literature on this important topic for readers new to the field. Chapter one provides exposure to the three-dimensional structure of proteins; readers will learn how to identify secondary structures, protein motifs, and domains involved in biological function. Chapter two introduces methodologies to determine the three-dimensional structure of proteins; readers will learn modern techniques to determine the secondary structure composition and the orientation of atoms in three-dimensional space. By providing exposure to how the physical environment (i.e., chemical denaturants, pH, pressure, and temperature) controls protein denaturation, readers will learn how such information can be used to study the biophysical characteristics of proteins through various probes and methodologies.

Book series logo
Detailed Table of Contents
About the Series
Preface
Chapter 1
Protein Folding
1.1
Introduction
1.2
Insider Q&A: Sir Alan Fesrsht
1.3
Insider Q&A: Paul Whitford
1.4
Insider Q&A: Ben Schuler
1.5
Insider Q&A: Jane Clarke
1.6
Timeline for Protein Folding
1.7
Proteins
1.7.1
Conformational Structure of Proteins
1.7.1.1
Protein Topology versus Geometry
1.7.1.2
Backbone Dihedral Angles
1.7.1.3
α-Helical Structures
1.7.1.4
β-Sheet Structures
1.7.1.5
Turns and Loops
1.7.1.6
Protein Motifs
1.7.1.7
Circular Permutations
1.7.1.8
Allosteric Control
1.8
Protein Folding and Free-Energy Landscape Theory
1.8.1
Mechanisms of Folding
1.8.2
Chaperones
1.8.3
Folding in the Cell
1.8.4
Cotranslational Folding
1.8.5
Fold-Switching Proteins
1.8.6
Intrinsically Disordered Proteins
1.9
Insider Q&A: Jane Clarke
1.10
Insider Q&A: Sir Alan Fesrsht
1.11
Protein Misfolding and Aggregation
1.11.1
The Protein Misfolding Funnel
1.12
Structure Prediction
1.12.1
Homology Modeling
1.12.2
Protein Design
1.12.3
Machine Learning
1.13
Insider Q&A: Pernilla Wittung-Stafshede
1.14
Insider Q&A: Paul Whitford
1.15
That’s a Wrap
Chapter 2
Biophysical Characterization of Proteins
2.1
Introduction
2.2
Structural Determination of Proteins
2.2.1
X-ray Crystallography
2.2.2
Cryogenic Electron Microscopy
2.2.3
Nuclear Magnetic Resonance
2.2.4
Small-Angle X-ray Scattering
2.2.5
Experimental Resolutions
2.3
Protein Denaturation
2.3.1
Disulfide Bonds in Proteins
2.4
Practical Methods and Probes
2.4.1
UV–Vis Absorption Spectroscopy
2.4.2
Spectrofluorometry
2.4.2.1
Fluorescence Probes
2.4.2.2
Fluorescence Resonance Energy Transfer
2.4.3
Circular Dichroism Spectroscopy
2.4.4
Infrared (IR) Spectroscopy and Raman Spectroscopy
2.4.5
Calorimetric Techniques
2.4.6
Analytical Ultracentrifugation
2.4.7
Ensemble versus Single-Molecule Folding Studies
2.5
Insider Q&A: Magnus Wolf-Watz
2.6
Insider Q&A: Ben Schuler
2.7
Thermodynamics Methodology and Analysis
2.7.1
Experimental Determination of ΔG
2.7.2
Deviation from Ideal Two-State Behavior
2.8
Kinetic Methodology and Analysis
2.8.1
Experimental Determination of Folding Kinetics
2.8.2
Chevron Plots
2.9
Insider Q&A: Sir Alan Fersht
2.10
Methodologies and Analysis of Transiently Formed States
2.10.1
Complex Folding
2.10.2
Phi-Value Analysis to Map the Transition-State Ensemble
2.11
Complex Protein Folding: A Funnel of Funnels
2.11.1
Funnel of Funnels
2.12
Concluding Remarks
2.13
That’s a Wrap
Bibliography
Glossary
Index
Author Info
Grace E. Orellana
Grace E. Orellana is a Ph.D. student at the Department of Chemistry at the University of Hawai‘i at Mānoa. She started her scientific career as an undergraduate researcher in Dr. Josh Sakon’s lab, studying the structural properties of collagenase at the University of Arkansas, where she also received her B.Sc. in Chemistry in 2020. Her expertise is in protein folding and function. Specifically, her research focuses on solving the molecular details regarding protein self-assembly and how misfolding may lead to disease.
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Ellinor Haglund
Ellinor Haglund is an Assistant Professor in the Department of Chemistry at the University of Hawai‘i at Mānoa. She received her M.S. in Chemistry and Molecular Biology at Umea University, Sweden, in 2004 and her Ph.D. from the Department of Biochemistry and Biophysics at Stockholm University, Sweden, in 2010. She completed postdoctoral training at the Center for Theoretical Biological Physics (CTBP) at the University of California at San Diego and Rice University before joining the University of Hawai‘i in 2018. Her research has been recognized by the NSF CAREER Award. She is inspired by how nature works and utilizes her multidisciplinary training to answer questions at the interface of chemistry, biology, and physics. Specifically, her research focuses on the folding and function of proteins with complex topologies, utilizing both computational and experimental techniques.
author image