<html><head></head><body style="word-wrap: break-word; -webkit-nbsp-mode: space; -webkit-line-break: after-white-space; color: rgb(0, 0, 0); font-size: 14px; font-family: Calibri, sans-serif; "><div><br></div><span id="OLK_SRC_BODY_SECTION"><div xmlns:v="urn:schemas-microsoft-com:vml" xmlns:o="urn:schemas-microsoft-com:office:office" xmlns:w="urn:schemas-microsoft-com:office:word" xmlns:x="urn:schemas-microsoft-com:office:excel" xmlns:dt="uuid:C2F41010-65B3-11d1-A29F-00AA00C14882" xmlns:m="http://schemas.microsoft.com/office/2004/12/omml" xmlns="http://www.w3.org/TR/REC-html40"><div lang="EN-US" link="blue" vlink="purple"><div class="WordSection1"><p class="MsoNormal"><o:p> </o:p></p><p class="MsoNormal" align="center" style="mso-margin-top-alt:auto;mso-margin-bottom-alt:auto;text-align:center;line-height:150%;background:white"><b><span style="font-size: 14pt; line-height: 150%; font-family: 'Times New Roman', serif; color: black; ">PhD DEFENSE STUDENT: </span></b><span style="font-size: 14pt; line-height: 150%; font-family: 'Times New Roman', serif; color: black; ">Katy Olafson</span><span style="font-family: 'Times New Roman', serif; color: black; "><o:p></o:p></span></p><p class="MsoNormal" align="center" style="mso-margin-top-alt:auto;mso-margin-bottom-alt:auto;text-align:center;line-height:150%;background:white"><b><span style="font-size: 14pt; line-height: 150%; font-family: 'Times New Roman', serif; color: black; ">DATE: </span></b><span style="font-size: 14pt; line-height: 150%; font-family: 'Times New Roman', serif; color: black; ">Tuesday, March 28, 2017</span><span style="font-family: 'Times New Roman', serif; color: black; "><o:p></o:p></span></p><p class="MsoNormal" align="center" style="mso-margin-top-alt:auto;mso-margin-bottom-alt:auto;text-align:center;line-height:150%;background:white"><b><span style="font-size: 14pt; line-height: 150%; font-family: 'Times New Roman', serif; color: black; ">TIME: </span></b><span style="font-size: 14pt; line-height: 150%; font-family: 'Times New Roman', serif; color: black; ">9:00 AM</span><span style="font-family: 'Times New Roman', serif; color: black; "><o:p></o:p></span></p><p class="MsoNormal" align="center" style="mso-margin-top-alt:auto;mso-margin-bottom-alt:auto;text-align:center;line-height:150%;background:white"><b><span style="font-size: 14pt; line-height: 150%; font-family: 'Times New Roman', serif; color: black; ">PLACE:</span></b><span style="font-size: 14pt; line-height: 150%; font-family: 'Times New Roman', serif; color: black; "> Bauer College of Business, Conference Room
302 - MH</span><span style="font-family: 'Times New Roman', serif; color: black; "><o:p></o:p></span></p><p class="MsoNormal" align="center" style="mso-margin-top-alt:auto;mso-margin-bottom-alt:auto;text-align:center;line-height:150%;background:white"><b><span style="font-size: 14pt; line-height: 150%; font-family: 'Times New Roman', serif; color: black; ">DISSERTATION CHAIR:
</span></b><span style="font-size: 14pt; line-height: 150%; font-family: 'Times New Roman', serif; color: black; ">Dr. Jeffrey Rimer and Dr. Peter Vekilov</span><span style="color:black"><o:p></o:p></span></p><div class="MsoNormal" align="center" style="text-align:center;line-height:150%;background:white"><span style="font-size: 10.5pt; line-height: 150%; font-family: Calibri, sans-serif; color: black; "><hr size="2" width="100%" align="center"></span></div><p class="MsoNormal" align="center" style="mso-margin-bottom-alt:auto;text-align:center;line-height:150%;background:white"><b><span style="font-size: 14pt; line-height: 150%; font-family: 'Times New Roman', serif; color: black; ">TITLE:<o:p></o:p></span></b></p><p class="MsoNormal" align="center" style="text-align:center;background:white"><b><span style="font-size: 14pt; font-family: 'Times New Roman', serif; color: black; ">Deciphering the Molecular Interactions between Antimalarials and Hematin Crystal Surfaces<o:p></o:p></span></b></p><p class="MsoNormal" align="center" style="text-align:center;background:white"><b><span style="font-size: 14pt; font-family: 'Times New Roman', serif; color: black; "><o:p> </o:p></span></b></p><p class="MsoNormal" style="text-align:justify;background:white"><span lang="EN-GB" style="font-family: 'Times New Roman', serif; color: black; ">The unique physicochemical properties of crystals are essential for a variety of commercial applications, consumer
products, and functional roles in diverse natural, synthetic, and biological systems. Facile methods of tailoring crystal properties, such as altering growth conditions, are characteristically inadequate and nontrivial. One versatile approach to control crystallization
involves the use of modifiers, which are additives that interact with crystal surfaces to alter their growth rates. Elucidating their binding specificity is a ubiquitous challenge that is critical to their design as well as understanding their role in natural
processes. In this dissertation project, we selected hematin, a pathological crystal that is relevant to malaria, as a model system to examine the complementarity of antimalarial drugs to crystal surfaces.</span><span style="font-size: 10pt; font-family: 'Times New Roman', serif; color: black; "><o:p></o:p></span></p><p class="MsoNormal" style="text-align:justify;background:white"><span style="font-family: 'Times New Roman', serif; color: black; "><o:p> </o:p></span></p><p class="MsoNormal" style="text-align:justify;background:white"><span style="font-family: 'Times New Roman', serif; color: black; ">Hematin is a byproduct of heme detoxification in malaria parasites. Current antimalarial compounds are thought to inhibit the growth
of hematin crystals, referred to as hemozoin (<i id="yui_3_16_0_ym19_1_1490014433256_353869">in vivo</i>) or b-hematin (<i id="yui_3_16_0_ym19_1_1490014433256_353871">in vitro</i>). Identification of antimalarial drug action on this phase transformation could
provide a foundation for drug design to overcome parasite resistance to antimalarials. Continued resurgence of antimalarial drug resistance drives research effort to better characterize drug-crystal interactions from a fundamental perspective. To this end,
we aim to better understand the molecular mechanism(s) of hematin crystallization and antimalarial drug action within physiologically-relevant environments as the basis for elucidating growth sites on hematin crystal surfaces and design more effective growth
inhibitors that selectively bind to these sites. </span><span style="font-size: 10pt; font-family: 'Times New Roman', serif; color: black; "><o:p></o:p></span></p><p class="MsoNormal" style="text-align:justify;background:white"><span style="font-family: 'Times New Roman', serif; color: black; "> </span><span style="font-size: 10pt; font-family: 'Times New Roman', serif; color: black; "><o:p></o:p></span></p><p class="MsoNormal" style="text-align:justify;background:white"><span style="font-family: 'Times New Roman', serif; color: black; ">We employ
<i id="yui_3_16_0_ym19_1_1490014433256_353876">in situ </i>atomic force microscopy (AFM) in parallel with bulk solution and crystallization studies as a platform to study the mechanisms of crystal growth and inhibitor-crystal interactions in biomimetic growth
solutions. Time-resolved <i id="yui_3_16_0_ym19_1_1490014433256_353877">in situ</i> AFM measurements reveal that hematin crystallization occurs by the classical pathway of single molecule incorporation, specifically involving two-dimensional nucleation and
layer-by-layer growth. Elucidating the growth pathway of hematin crystals in a physiologically relevant medium shows the active sites on the surfaces. These become ideal target sites for suppressing crystal growth through the introduction of modifiers (i.e.,
antimalarials). Extended studies showed that molecules incorporate through surface diffusion that leads to reduced step velocity at interstep distances
<i>l</i> < 180 nm. Crystallization involving surface diffusion creates a model system to study the early onset of roughening. We identified new parameters for understanding supersaturations that result in a transition to rough growth.</span><span style="font-size: 10pt; font-family: 'Times New Roman', serif; color: black; "><o:p></o:p></span></p><p class="MsoNormal" style="text-align:justify;background:white"><span style="font-family: 'Times New Roman', serif; color: black; "> </span><span style="font-size: 10pt; font-family: 'Times New Roman', serif; color: black; "><o:p></o:p></span></p><p class="MsoNormal" style="text-align:justify;background:white"><span style="font-family: 'Times New Roman', serif; color: black; ">Our studies of antimalarials as modifiers has led to the identification of their unique modes of inhibition on hematin crystal growth:
step pinning, kink blocking, and macro-step induction. Towards understanding the functional moieties responsible for controlling the inhibition mode, we examined antimalarial compounds, including specific functional groups and constituents, by
<i id="yui_3_16_0_ym19_1_1490014433256_353883">in situ</i> AFM and chemical force microscopy measurements on hematin {100} crystal faces. Our findings reveal unique properties of antimalarials that govern their efficacy. Identifying fundamental principles governing
the molecular recognition of antimalarial drugs to specific sites could lead to the rational design of new compounds with improved efficiency to overcome parasite resistance to current antimalarials.</span><span style="font-size: 10pt; font-family: 'Times New Roman', serif; color: black; "><o:p></o:p></span></p><p class="MsoNormal" align="center" style="mso-margin-top-alt:auto;mso-margin-bottom-alt:auto;text-align:center;line-height:150%;background:white"><span style="font-family: 'Times New Roman', serif; color: black; "><o:p> </o:p></span></p><p class="MsoNormal"><o:p> </o:p></p></div></div></div></span><style><!--
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