Computational Design of Protein-Ligand Interfaces Using Rosettaligand
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Computational Design of Protein-Ligand Interfaces Using RosettaLigand By Brittany Ann Allison Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Chemistry May, 2016 Nashville, Tennessee Approved: Jens Meiler, Ph.D. Brian O. Bachmann, Ph.D. John A. Capra, Ph.D. Michael P. Stone, Ph.D. To my parents, Warren and Talita Allison, and my sister Kelly Thank you for always believing in me iii ACKNOWLEDGEMENTS To Vanderbilt University and especially the Department of Chemistry, thank you for the opportunity and supporting me in my time as a doctoral student. To earn a PhD in chemistry is no small feat, and I am thankful for all the resources and continued support from faculty and staff in the department who have helped me along the way. Vanderbilt is an outstanding research institution, and I am grateful to have completed my doctoral studies here. To Jens Meiler, my PhD advisor, thank you for everything. Thank you for not only the opportunity to be a research student in your lab, but for actually supporting and guiding me for the past 6 years. This experience would not be the same without you. Since the day we met at the CSB gathering in November/December 2009, one of my favorite memories during my time here, thank you for always inspiring me and being committed to my success as a phD student. Thank you for pushing me outside of my comfort zone. Thank you for recognizing my talents and helping me to develop them. When I needed to push harder you always let me know, but it was in an energizing way, which left me excited to keep going. Thank you for developing my career interests and allowing me to pursue avenues to enhance these, such as teaching opportunities on campus and attending conferences. Traveling together to my undergrad institution for my research presentation, another one of my favorite memories, was a two-fold amazing experience as an alum and also as a PhD student. I am grateful to be in a lab where we share scientific knowledge as well as fun times, and I enjoyed the lab outings, retreats, holiday socials, and lab gatherings at your house. Thank iv you for the fun stories you share and for the random chit-chats. Thank you for always reminding me to “push forward” towards the goal. Jens, your continued insight and encouragement have left a lasting imprint on me, and I will always appreciate having such a great PhD advisor. To my committee members, Brian Bachmann, Tony Capra, and Mike Stone, thank you for guidance and input in my research as I matriculated through the years. Your help in scheduling meetings and presence at my exams has been greatly appreciated. Thank you for being on board to support my doctoral studies. I look forward to keeping you updated as I progress in my career. I would like to thank my past committee members Richard Armstrong (deceased) and Laura Mizoue for their investment in me as well. Thank you to the Director of Graduate Studies, Carmelo Rizzo, for readily proving information about the PhD journey. To my parents, Warren and Talita Allison, and my sister Kelly, you are the reason I never gave up. I could not have done this without you and God in my corner on a daily basis. All my life you have been my number one supporters, and because of you I have been able to achieve every time. Thank you for instilling confidence in me from a young age. I always remember being told, from very young up to just a few hours ago, “You can do this Britt!”, and you have always being right. Your love, encouragement, support, insight, phone calls, guidance, and prayers have allowed me to overcome every challenge I encountered in my PhD journey. From the moment I was accepted to Vanderbilt, you continuously told me I would make it to the end, and I have. Along the way, you have provided unwavering support as I made it through difficult graduate classes, my pre-qualifying exam, my qualifying exam, stressful poster presentations and oral presentations in the department and at conferences, my independent research proposal exam, and now in defending my dissertation. And I know v this support will continue as I begin my journey as a post-doc, and then on to career positions. Thank you for always being invested in my dreams, and encouraging me to do whatever it takes to achieve them. I am who I am, because of who you are. Daddy, thank you for reminding me to keep “Faith, family, and focus” near to me, no matter what else is going on, and that with faith and God by my side, I have what it takes to press forward. Thank you reminding me to recognize all the family members who are invested in my success, especially my grandparents who send love and prayers my way daily. And thank you for always being a source of wisdom and kindness, whenever I need to refocus my balance and get back on track. Momma, thank you continuously telling me “You are closer than you think”. Often times, the goal seemed so far away, but you always readjusted my thinking into positive thoughts so that I could see my little milestones along the way. Thank you for reminding me that our family background is strong, therefore I am strong too. And thank you for the long phone conversations about life, which I always needed as a good distraction. Kelly, my sister and best friend, thank you for always telling me to “Stop stressing you want to be the best, but KNOW you will do your best, and it will be great”. This has often carried me as I strive to be the best graduate student I can be. Thank you for always loving and supporting me and listening to my random stories and offering thoughtful advice, even when you have a lot on your plate too. It means so much. And thank you for all the fun we have and inside jokes we share, whether at home or on the phone or via text message, these get me through on a daily basis. My family, I love you three very much and I am so thankful, and so blessed, to always have you in my corner and in my life. It makes me proud to know that you are proud of me. On campus, I have received tremendous support from various people and institutes. Thank you to the Meiler Lab, my lab home since March 2010, for amazing science, valuable vi research insight, and awkward science humor. A special thanks to Amanda Duran and Steffen Lindert for being supportive lab members as well as friends, and for the walks outside. Thank you to Heather Darling, Caitlin Harrison, and Xuan Zhang for being a great help in the wet lab. Thank you to the Vanderbilt Institute of Chemical Biology (VICB) for awarding me my first year fellowship and the training grant for my second and third years. I participated in many VICB events over the years, which were beneficial and enjoyable. Amanda Renick and Michelle Sulikowski provided much encouragement, help, and mentorship during these years. Thank you to the Center for Structural Biology (CSB) for providing many CSB associated resources that I use for my research and the administrative support team, especially Karen Davis. Thanks to the Biomolecular NMR facility and Markus Voehler for assistance in my research. Thank you to Sandra Ford in the chemistry department, for answering my questions and for always being a friendly face. Thank you to Dean Ruth Schemmer for the amazing career development workshops, which I often attend. Thank you to Dean Elizabeth Rapisarda for being the point of contact for my NSF-GRFP fellowship. Thank you to Dean Don Brunson for connecting me with many great minority graduate students on campus and for your work in recruiting minority students to pursue a PhD at Vanderbilt. Thank you to the Center for Teaching for hosting teaching workshops and for the college teaching course. Thank you to the Programs for Talented Youth for allowing me the opportunity to teach and share my research with 7th and 8th graders. Thank you to the Graduate Student Council for the fun social events. Thank you to the Office of Black Graduate and Professional Students (OBGAPS), Alliance for Cultural Diversity in Research, and Black Cultural Center, for all providing support and friendships in various ways as a black woman vii pursuing a PhD. I am thankful to be on a campus where I could connect with people who share experiences similar to myself. Off campus, I have received great support as well. Thank you to the National Science Foundation Graduate Research Fellowship Program for awarding me their prestigious fellowship, which supported me in my last three years and allowed me the opportunity to present my research at many conferences. Thank you to the Rosetta Commons for being a community of scientists to engage with and gain valuable insight on the computational side of my project. Thank you to the National Organization of Black Chemists and Chemical Engineers (NOBCChE), for being not only a scientific community but a community to share experiences. I am very thankful for all the connections and guidance I receive from being a part of NOBCChE. Thank you to my undergraduate institution, Xavier University of Louisiana, especially the chemistry department, for showing me continued encouragement in my time here at Vanderbilt.