Table Of ContentBinding Affinity of a Small Molecule
to an Amorphous Polymer in a Solvent
by MASSACHUSETTS INSTIT
OF TECHNOLOGY
Surasak Chunsrivirot
JUN 14 2 011
B.S. Chemistry with a Biology Minor
B.S. Computer Science and Engineering LIBRARIES
Massachusetts Institute of Technology, 2006
SUBMITTED TO THE COMPUTATIONAL AND SYSTEMS BIOLOGY
PROGRAM IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR
THE DEGREE OF
ARCHNES
DOCTOR OF PHILOSOPHY
AT THE
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
JUNE 2011
© Massachusetts Institute of Technology 2011. All rights reserved.
Signature of Author:
Computational and Systems Biology Program
May 5* , 2011
Certified by: May th 2011
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Bernhardt Trout
Professor of Chemical Engineering
Thesis Supervisor
Accepted by.
iunistopher Burge
Associate Professor of Biology
Director, Computational and Systems Biology Graduate Program
Binding Affinity of a Small Molecule to
an Amorphous Polymer in a Solvent
by
Surasak Chunsrivirot
Submitted to the Computational and Systems Biology Program
on May 1 th, 2011 in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy
ABSTRACT
Crystallization is a commonly used purification process in industrial practice. It usually begins
with heterogeneous nucleation on a foreign surface. The complicated mechanism of
heterogeneous nucleation is not well understood, but we hypothesize a possible correlation
between binding affinity to a surface and nucleation enhancement. Amorphous polymers have
been used in controlling crystallization. However, to our knowledge no attempt has been made to
investigate the possibility of using binding affinity to help guide the selection of polymers
promoting heterogeneous nucleation. This study investigated the possibility of using binding
affinity of one molecule and many molecules to help guide the selection of these polymers. To
measure the binding affinity of one molecule, we developed a two-step approach to compute the
free energy of binding to a binding site, using a system of ethylene glycol, polyvinyl alcohol
(PVA), and heavy water (D 0). The first step of our approach uses Adsorption Locator to
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identify probable binding sites and molecular dynamics to screen for the best binding sites. The
second step employs the Blue-Moon Ensemble method to compute the free energy of binding.
We then applied our procedure to the systems of aspirin binding on the surfaces of four non-
porous crosslinked polymers in ethanol-water 38 v%. These polymers are poly(4-
acryloylmorpholine) (PAM), poly(2-carboxyethyl acrylate) (PCEA), poly(4-hydroxylbutyl
acrylate) (PHBA), and polystyrene (PS), and they all are crosslinked with divinylbenzene
(DVB). We developed an approach to construct these crosslinked polymers and built three
independent surfaces for each polymer. We found the similarity between the trend of
heterogeneous nucleation activity and that of the average free energies of binding to the best site
of each polymer surface. To measure the binding affinity of many molecules, preferential
interaction coefficient and the number of aspirin molecules associated with the area of the
binding site was calculated. We found that there is also a similarity between the trend of
heterogeneous nucleation activity and that of number of aspirin molecules associated with the
area of the binding site (taken into account the effects of polar/apolar atom interactions between
an aspirin and a polymer). These results suggest the possibility of using binding affinity,
especially the free energy of binding to the best site and the number of nucleating molecule, to
help guide the selection of polymers promoting heterogeneous nucleation.
Thesis Supervisor: Bernhardt L. Trout
Title: Professor of Chemical Engineering
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This thesis is dedicated to my mother, belatedf ather and my elder brothers,
who made sacrifices so that I could have the opportunity
to pursue the highest education possible.
This MIT Ph.D. thesis is for you.
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Acknowledgements
I would like to thank my thesis supervisor Professor Bernhardt L. Trout for his thoughtful
guidance and research ideas. I am also very thankful to my thesis committee Prof. T. Alan
Hatton, Prof. Gregory C. Rutledge, Prof. Collin M. Stultz and Prof. Allan Myerson for their help
and useful insights.
I would like to also thank the members of the Trout group. Ying Diao helped and provided me
with the experimental data. Dr. Erik Santiso taught me how to implement the Blue-Moon
Ensemble method, helped me with the order parameter analysis, and provided me very useful
advice and discussion on my research, career and publications. Diwakar Shukla gave me advice
on the calculation of the preferential interaction coefficient. Nick Musolino and Tim Lauer set up
and maintained the computer clusters, and helped me when I had technical problems with the
clusters. Dr. Jie Chen and Dr. Gregg T. Beckham initially helped me get started with molecular
simulations. Dr. Veysel Kayser gave me career advice and words of encouragement throughout
my Ph.D. studies. Angelique, Connie and Stephanie helped me with administrative matters.
Moreover, I am very grateful for the Computational and Systems Biology Program, the
previous/current director and staff such as Prof. Bruce Tidor, Prof. Chris Burge, Darlene Ray and
Bonnie Lee Whang. I am also very thankful to the Writing and Communication Center staff, who
helped me not only with this thesis, but also with my journal articles, presentations, and thesis
proposal through the years. These staff are Amanda, Susan, Thalia, Bob, Rob, Prof. Steve Strang
(the director who introduced me to the center), etc.
I am also indebted to the Computational and Systems Biology Fellowship and the Novartis-MIT
Center for Continuous Manufacturing for financial support during my studies.
During my time at MIT, I also benefited from many great friendships and I am very thankful to
my friends who are very kind and thoughtful. During my Ph.D. studies, they supported and
encouraged me to overcome all the difficult challenges. Listed in alphabetical order, these great
friends are as follows. Dr. Ahmet Turan Ozdemir is my old roommate, my friend and my long-
lost brother in Kayseri Turkey. He first introduced me to the wonderful culture, people and
country of Turkey. When I visited Turkey and attended his wedding, he took a great care of me,
hosted me and showed me many cities such as Kayseri, Istanbul and Malatya. Ahmet Kerim
Agirman has a great sense of humor. He likes making funny comments on Facebook and during
conversions. He often makes funny poses whenever his picture is taken. To surprise me, he came
to New York and met me at Times Square to countdown to the year 2011, my last year in
America, and endured the coldness with me, while waiting seven hours for the countdown.
Hasan Ilhan is a very funny friend, whom I sometimes call "Yalanci Qoban." Putting his jokes
aside, he is one of a very few people who shares similar childhood experience with me. Maybe
that is why we get along very well. During my last few months in America, I am glad to have
had a chance to spend more time with him since he moved to Boston to continue his Ph.D. Ismail
Balci is my best hemgo, who has a great sense of humor as shown in his comments during
conversations or on Facebook. Always happy and smiling in spite of the circumstances, he is
easily the most positive person I ever met. He also made me feel like I was home with my close
friends in Thailand. Often, I spent time playing Monopoly and other games with him and his
housemates at his apartment. He is one of the most selfless persons I have ever met. He always
helps other people in need even though at the time he does not have enough time to complete his
own work and other responsibilities. Kemal Keskin, a funny guy who is now in Eskigehir,
introduced me to Turkish friends and Turkish communities in Boston. While he was in Boston,
we did lots of fun activities and shared wonderful memories together. Mahmut Guven has always
been a great friend, who operated an unofficial hotel at his house and often invited me to have
dinner and stay over. Mehmet Emin OztUrk gave me a crash course in Turkish. Mustafa Gedik
helped me write cards to my friends in Turkish. Nattapol Ploymaklam (Tape) is a very thoughtful
and supportive friend in Iowa, whom I called very often to share my life experience and
obstacles. He has been a great support throughout my Ph.D. studies. Thank you so much for
everything Tape. Patricio Ramirez gave me very helpful advice on Ph.D. studies. Ahmet Belli,
Gultekin Tasdirek, Mahmut Guven, and Kemal Keskin are great chefs, whom I told to open their
own restaurants someday. There are also many other great friends in Boston, whose friendships I
will always cherish. I would like to also thank Abdulkadir, Bakir, Ebubakir, Emrah Korkmaz,
Hasan Altunbus, Lohith, Melih Ecertas, Mint, Mustafa Bakir, Racip, Sehmug, Ufuk Muncuk,
Victor, Yasin Kaymaz, and other friends that I may have forgotten to mention. You all made me
feel at home and gave me memorable experiences. I am very grateful for your friendships. I am
also very grateful for the Turkish Cultural Center (TCC) and Turkish community in Boston, who
welcomed and treated me with warmth and love. I want to especially thank Vaner Kaplan, one of
the staff at TCC, for his kindness, generosity, friendship and his helping my friends to settle in
America. Moreover, I also want to thank the owner and the friendly staff of Inbound Pizza, who
are very kind and welcoming. Inbound Pizza is one of my favorite places in Boston, where I had
great conversations and wonderful memories with my friends.
I am also grateful for my friends in Turkey, Thailand, Germany and England. I met lots of
wonderful people, who took a great care of me when I visited Turkey in 2008 and 2009. G6kgen
and Umut Ozdemir in Kayseri are great friends, who hosted me and took me to see and enjoy the
city of Kayseri. Dr. Mustafa Turkmen, who is currently doing a post-doc in Boston, has been a
great friend. I spent a lot of time doing various activities with him and his family in Kayseri and
in Boston. Dr. Nurettin Ustkoyuncu, who is currently doing a post-doc in Virginia, is easily one
of the kindest and most caring persons I ever met. I spent my last Christmas break in America
with him and it was probably my most memorable Christmas. He also makes great coffee and
hot chocolate; that is why I called his office in Turkey/his apartment in Virginia Nurettinbucks!
Additionally, I want to thank the family of Ahmet Turan, Nurettin, Emrah, and Kemal who were
very hospitable, welcoming, kind and loving. They took great care of me as if I were a member
of their families, when I visited Turkey. Hopefully, I will have a chance to visit you all in Turkey
again.
In Thailand, I am also very fortunate to have many great friends, who are very kind and
supportive. I often called them on the weekends to catch up and discuss our lives and our friends'
lives. They helped support me and gave me words of encouragement throughout my difficult
times. These friends are as follows. Thammanit Hattaya is one of my best friends from junior
high school, Kanthalakwittaya School, in my small hometown in Kanthralak, Sisaket, Thailand.
Peecha Rattanakowin is one of my best friends from high school (Triam Udom Suksa School,
Bangkok). Since he is a doctor, sometimes I even got some medical advice from him when I got
sick. Another one of my best friends since high school is Wanlop Atsariyasing. He is one of the
most positive people I have ever met, probably why he later became a psychiatrist. I also want to
thank him for praising me for being able to overcome all the challenging obstacles in my Ph.D.
and in my life on my own. Another one of my best friends from high school is Attakrit
Leckcivilize, who is currently doing his Ph. D. in London. He is selfless, and he always has a
very positive look on life. I would like to also thank him for visiting me in Boston. Mrs.
Phensophit Mayer, who currently resides in Germany, always supported me and gave me kind
words of encouragement during my difficult times. I am also grateful for other friends in
Thailand such as Kerati Prasertphol, Kraisoon Lomjansook, Porwanad Saengsuri, Oranich
Navanukroh, Nadya Jai, Chairit Lohakitsathian, Pisit Wanicha, Werawut Pattanaworapong,
Khacha Somchai, Chawantat Saard, Apilak Aromseree, Suparat Meekhun, Siriwan Samran, and
other friends whom I may have forgotten to mention. Just wait. In a few months, I will go back
home and meet you all again.
Finally, none of this would have been possible without the love and support of my parents and
my elder brothers. I am very grateful to my mother and my belated father. Due to the financial
situations of their families, my belated father did not have an opportunity to go to high school,
and my mother did not have a formal education. Despite their limited education and financial
resources, they always encouraged me to pursue the highest education possible. My mother
always supports and loves me unconditionally. When I find myself in times of trouble or facing
difficult challenges, she often says "be strong and be patient and you will overcome all the
obstacles." I am also very grateful to my three elder brothers. After the death of my father in a
motorcycle accident when I was about eight, they sacrificed their educational opportunities,
dropping out of high school to run our small family business, so that I had an opportunity to
pursue the highest possible education.
I would like to dedicate this thesis to my mother, belated father and my elder brothers, to whom I
am eternally grateful. This MIT Ph.D. thesis is for you.
Surasak Chunsrivirot
April 2011
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Description:Another one of my best friends from high school is Attakrit. Leckcivilize, who is currently doing his Ph. D. in London. He is selfless, and he always has a.
