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Multiscale Simulations of Intrinsically Disordered Proteins University of Massachusetts Amherst ScholarWorks@UMass Amherst Doctoral Dissertations Dissertations and Theses July 2019 Multiscale Simulations of Intrinsically Disordered Proteins Xiaorong Liu University of Massachusetts Amherst Follow this and additional works at: https://scholarworks.umass.edu/dissertations_2 Part of the Biophysics Commons, Physical Chemistry Commons, and the Structural Biology Commons Recommended Citation Liu, Xiaorong, "Multiscale Simulations of Intrinsically Disordered Proteins" (2019). Doctoral Dissertations. 1565. https://doi.org/10.7275/14020756 https://scholarworks.umass.edu/dissertations_2/1565 This Open Access Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks@UMass Amherst. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of ScholarWorks@UMass Amherst. For more information, please contact [email protected]. Multiscale Simulations of Intrinsically Disordered Proteins A Dissertation Presented by XIAORONG LIU Submitted to the Graduate School of the University of Massachusetts Amherst in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY May 2019 Chemistry © Copyright by Xiaorong Liu 2019 All Rights Reserved Multiscale Simulations of Intrinsically Disordered Proteins A Dissertation Presented by XIAORONG LIU Approved as to style and content by: ____________________________________ Jianhan Chen, Chair ____________________________________ Scott Auerbach, Member ____________________________________ Craig Martin, Member ____________________________________ Li-Jun Ma, Member __________________________________ Richard Vachet, Department Head Department of Chemistry DEDICATION To my parents, husband, advisor and other educators who light the way forward for me. ACKNOWLEDGMENTS First and foremost, I would like to express my wholehearted gratitude to my research advisor Dr. Jianhan Chen. Dr. Chen is a great scientist, who is extremely knowledgeable, wise and passionate about science. His dedication, open mindedness, and critical thinking greatly impact us. He is also a fantastic mentor, willing to share his knowledge, insights and experience with us, and incredibly supportive in our personal and career development. My graduate school journey couldn’t be so rewarding and happy without his patient guidance, generous support, and continuous encouragement. I couldn’t imagine having a better advisor for my PhD study, and it’s my great honor to be his student. I am also very grateful to other members in my dissertation committee, Dr. Scott Auerbach, Dr. Craig Martin and Dr. Li-Jun Ma. Their insightful comments and great suggestions always inspire me. I also want to thank our collaborators, Dr. Michal Zolkiewski and Dr. Om Prakash and Dr. Chungwen Liang for all of their help and encouragement. I’m blessed to have had the opportunity of working in a wonderful research group. Many thanks to my labmates in Dr. Chen’s lab: Dr. Zhiguang Jia, Dr. Kuo Hao Lee, Dr. Mara Chiricotto, Dr. Charles English, Dr. Azar Farjamnia, Dr. Weihong Zhang, Dr. Debabani Ganguly, Mahdieh Yazdani, Xiping Gong, Erik Nordquist, Lynn Schrag, Alex Beugelsdijk, Katrina Nguyen, Justin Campbell and Minh Ho. Their friendship, generous help, and stimulating discussion are greatly appreciated. Last but not least, I am deeply indebted to my parents and my husband for their support and sacrifice. Their unconditional love, meticulous care, and full trust have nourished my life and encouraged me to move forward. v ABSTRACT MULTISCALE SIMULATIONS OF INTRINSICALLY DISORDERED PROTEINS MAY 2019 XIAORONG LIU B.S., WUHAN UNIVERSITY, CHINA M.S., WUHAN UNIVERSITY, CHINA M.A., UNIVERSITY OF DELAWARE Ph.D., UNIVERSITY OF MASSACHUSETTS AMHERST Directed by: Professor Jianhan Chen Intrinsically disordered proteins (IDPs) lack stable secondary and/or tertiary structures under physiological conditions. The have now been recognized to play important roles in numerous biological processes, particularly cellular signaling and regulation. Mutation of IDPs are frequently associated with human diseases, such as cancers and neuron degenerative diseases. Therefore, it is important to understand the structure, dynamics, and interactions of IDPs, so as to establish the mechanistic basis of how intrinsic disorder mediates versatile functions and how such mechanisms may fail in human diseases. However, the heterogeneous structural ensembles of IDPs are not amenable to high resolution characterization solely through experimental measurements, and molecular modelling and simulation are required to study IDP structures, dynamics, and interactions at the atomistic levels. Here, we first applied the state-of-the-art explicit solvent atomistic simulations to an anti- apoptotic protein Bcl-xL and demonstrated how inherent structural disorder may provide a vi physical basis of protein regulated unfolding in signaling transduction. We have also constructed a series of efficient coarse-grained models to directly simulate the interactions between IDPs and unveiled how the preexisting structural elements accelerate binding of ACTR to NCBD by promoting efficient folding upon encounter. These studies shed important light on how IDPs perform functions in the cellular regulatory network, but also reveal the necessity of new sampling techniques for more efficient simulations of IDPs. We have thus developed a novel sampling technique, called multiscale enhanced sampling (MSES). MSES couples the atomistic model with coarse-grained ones, to accelerate the sampling of atomistic conformational space. Bias from coupling to a coarse-grained model can be removed using Hamiltonian replica exchange. To achieve the best possible efficiency of MSES simulations, we have developed a new hybrid resolution protein model that could capture the essential features of IDP structures, so as to generate local and long- range fluctuations that are largely consistent with those at the atomistic level. We have also developed an advanced replica exchange protocol, to allow the fast conformational transitions observed in the coupled conditions to be rapidly exchanged to the unbiased limit. Application of these strategies to characterize the structural ensembles of a few non- trivial IDPs shows that faster convergence rate can be achieved, demonstrating the great potential of MSES for atomistic simulations of larger and more complex IDPs. vii TABLE OF CONTENTS Page ACKNOWLEDGMENTS ...................................................................................................v ABSTRACT ....................................................................................................................... vi LIST OF TABLES ............................................................................................................. xi LIST OF FIGURES ......................................................................................................... xiii CHAPTER 1. INTRODUCTION ...................................................................................................1 1.1 Intrinsically disordered proteins: structure, dynamics, and interaction .............1 1.1.1 Key properties and functional advantages of IDPs .............................2 1.1.2 Experimental methods towards characterizing IDP structures ...........3 1.1.3 Experimental methods for studying IDP interactions .........................4 1.1.4 Challenges in experimental studies of IDPs .......................................5 1.2 Molecule modeling and simulations in studying IDPs ......................................6 1.2.1 Computational studies of IDP structure and dynamics .......................7 1.2.2 Computational studies of IDP interactions .........................................8 1.2.3 Limitations in computational approaches ...........................................9 1.3 Advances and challenges in simulating IDPs ..................................................10 1.3.1 Advances in force field development ...............................................10 1.3.2 Development of enhanced sampling methods ..................................11 1.4 Dissertation Outline .........................................................................................13 2. DYNAMICS OF THE BH3-ONLY PROTEIN BINDING INTERFACE OF BCL-XL .......................................................................................................................15 2.1 Introduction ......................................................................................................16 2.2 Methods............................................................................................................19 2.3 Results and Discussion ....................................................................................22 2.3.1 Analysis of existing PDB structures of Bcl-xL.................................22 2.3.2 Stability and fluctuation of simulation trajectories ...........................26 2.3.3 Conformational dyanamics of the BH3-only Protein Binding Interface .........................................................................................29 2.4 Conclusions ......................................................................................................32 2.5 Supporting Material .........................................................................................34 viii 3. ENHANCED SAMPLING OF INTRINSIC STRUCTURAL HETEROGENEITY OF THE BH3-ONLY PROTEIN BINDING INTERFACE OF BCL-XL .......................................................................................................................46
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