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Large Protein Folding and Dynamics Studied by Advanced Hydrogen Exchange Methods University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2013 Large Protein Folding and Dynamics Studied by Advanced Hydrogen Exchange Methods Benjamin Thomas Walters University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Analytical Chemistry Commons, Biochemistry Commons, and the Biophysics Commons Recommended Citation Walters, Benjamin Thomas, "Large Protein Folding and Dynamics Studied by Advanced Hydrogen Exchange Methods" (2013). Publicly Accessible Penn Dissertations. 937. https://repository.upenn.edu/edissertations/937 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/937 For more information, please contact [email protected]. Large Protein Folding and Dynamics Studied by Advanced Hydrogen Exchange Methods Abstract Protein folding studies over the past 50 years have been largely focused on small proteins (< 200 residues) leading to a dearth of information about large protein folding. Regardless of protein size, research has generally lacked the structural tools with necessary temporal resolution to provide mechanistic insight into the process. This goal requires incisive information on transient kinetic intermediate conformations that describe the folding pathway. In this work special challenges that hinder large protein folding studies are addressed, and advancements to both HX NMR and HX MS experiments are described that provide unparalleled temporal resolution of structure formation than has been previously possible. These various advanced hydrogen exchange methods are used to study folding behaviors of the large, 370-residue, two-domain maltose binding protein from E. coli and provide a description of its folding pathway in structural detail. This work sheds light on two basic unresolved problems regarding the mechanisms of protein folding, the first being the enigmatic nature of the initial folding collapse event seen in many proteins, and the second concerning the nature of the folding pathway. We find that from an initially heterogeneous hydrophobic collapse, an obligatory intermediate emerges with a 7-second time constant followed by an apparent sequential pathway to the native state. These results add the largest protein studied at structural resolution to-date to the list of proteins known to fold through obligatory, native-like intermediates in distinct pathways and this work highlights strategies that may be employed to interrogate other large systems in future work. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Biochemistry & Molecular Biophysics First Advisor S. Walter Englander Second Advisor Feng Gai Keywords Collapse, Denatured State Ensemble DSE, HDX MS, Hydrogen Exchange, Maltose Binding Protein, Protein Folding Subject Categories Analytical Chemistry | Biochemistry | Biophysics This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/937 LARGE PROTEIN FOLDING AND DYNAMICS STUDIED BY ADVANCED HYDROGEN EXCHANGE METHODS Benjamin Thomas Walters A DISSERTATION in Biochemistry and Molecular Biophysics Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2013 Supervisor of Dissertation _________________________________ S. Walter Englander, Ph.D. Jacob Gershon-Cohen Professor of Medical Science Professor of Biochemistry and Biophysics Graduate Group Chairperson __________________________________ Kathryn M. Ferguson, Ph.D. Associate Professor of Physiology Dissertation Committee: Feng Gai, Ph.D., Professor of Chemistry (Chair) Kim Sharp, Ph.D., Associate Professor of Biochemistry and Molecular Biophysics Ben E. Black, Ph.D., Associate Professor of Biochemistry and Molecular Biophysics Jeffery G. Saven, Ph.D., Associate Professor of Chemistry Bohdana M. Discher, Ph.D., Research Assistant Professor of Biochemistry and Biophysics Michael B. Goshe, Ph.D., Associate Professor of Biochemistry, North Carolina State University LARGE PROTEIN FOLDING AND DYNAMICS STUDIED BY ADVANCED HYDROGEN EXCHANGE METHODS COPYRIGHT 2013 Benjamin Thomas Walters This work is licensed under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 License To view a copy of this license, visit: http://creativecommons.org/licenses/by-ny-sa/2.0/ Dedication To my wife, Lindsey, who has shown me the meaning of the word dedication in her patience and support of me over the past six years. iii ACKNOWLEDGMENT My undergraduate biochemistry professor, Michael B. Goshe, inspired me to pursue this Ph.D. If he had not pulled me aside as a senior at NCSU and suggested that I work in his lab, I would not be here today. He has tremendously influenced my life. This work would not have been a success without my mentors Walter Englander and Leland Mayne. They taught me how to be a scientist, how to improve my writing for scientific audiences, how to be a skeptic, how to study protein folding, about the wonderful world of HX, and, most importantly, that no data is better than bad data. Second to them are Josh Wand and John Gledhill. As a first-year graduate student I rotated with Josh Wand’s group. His graduate student, John Gledhill, inspired me to learn how to computer program, and patiently answered all of my questions. This skill proved to be one of the most valuable in my time at Penn. I also appreciate the Wand wet lab team who provided me with unpurified MBP for the studies described in this work. My thesis committee has been an integral part of advising me throughout my time at the University of Pennsylvania. Permanent members include Feng Gai (chair), Kim Sharp, Ben Black, and Jeffrey G. Saven. Michael Ghoshe and Bohdana Discher kindly agreed to externally and internally review this work, respectively. I am grateful for their help and guidance over the past years. My lab mates: John Skinner, Alec Ricutti, Zhong-Yuan Kan, Wenbing Hu, and Palaniappan Chetty made the experience a pleasure. I enjoyed many helpful discussions and learned many things from them. The members of Josh Wand’s lab who taught me NMR, namely Kathy Valentine and John Gledhill. Additionally, Sabrina Bédard, Nathaniel Nucci, Vonni Moorman, Jacob Dogan, Joseph Kielic, helped when I needed assistance and we had many useful discussions. The Wand wet lab provided needed protein when I had run out, this was wonderful and very nice of them. We had a fruitful collaboration with the Sosnick lab at the University of Chicago. Their criticisms and assistance collecting SAXS data helped solidify the reality of our findings in Chapter 5. James Henshaw helped me process and understand the SAXS data. My family has also provided a wonderful support network to help me through the harder times and celebrate the good times. I want to thank my wife, Lindsey Walters; my mom and dad, Diane and Edward Walters; my brother, Kevin Walters; my uncle Robert Gray; and my grandmothers, “Mema” (Marie Gray) and “Granny” (Joanne Walters). I deeply appreciate my wonderful mother in particular for helping me proofread this text. This work was supported by National Institutes of Health research grants RO1 GM031847 (to S.W.E) and a structural biology pre-doctoral training grant GM08275 (to B.T.W.), and a National Science Foundation research grant MCB1020649 (to S.W.E.). Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357. This project was supported by grants from the National Center for Research Resources (2P41RR008630-18) and the National Institute of General Medical Sciences (9 P41 GM103622-18) from the National Institutes of Health. iv ABSTRACT LARGE PROTEIN FOLDING AND DYNAMICS STUDIED BY ADVANCED HYDROGEN EXCHANGE METHODS Benjamin Thomas Walters S. Walter Englander Protein folding studies over the past 50 years have been largely focused on small proteins (< 200 residues) leading to a dearth of information about large protein folding. Regardless of protein size, research has generally lacked the structural tools with necessary temporal resolution to provide mechanistic insight into the process. This goal requires incisive information on transient kinetic intermediate conformations that describe the folding pathway. In this work special challenges that hinder large protein folding studies are addressed, and advancements to both HX NMR and HX MS experiments are described that provide unparalleled temporal resolution of structure formation than has been previously possible. These various advanced hydrogen exchange methods are used to study folding behaviors of the large, 370-residue, two-domain maltose binding protein from E. coli and provide a description of its folding pathway in structural detail. This work sheds light on two basic unresolved problems regarding the mechanisms of protein folding, the first being the enigmatic nature of the initial folding collapse event seen in many proteins, and the second concerning the nature of the folding pathway. We find that from an initially heterogeneous hydrophobic collapse, an obligatory intermediate emerges with a 7- second time constant followed by an apparent sequential pathway to the native state. These results add the largest protein studied at structural resolution to-date to the list of proteins known to fold through obligatory, native-like intermediates in
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