Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2013 Solvent effects in quantum chemical-based methods : I. defined-sector explicit solvent in the continuum model approach for computational prediction of PKa and II. algorithmic strategies towards inclusion of first solvation shell effects Abramson, Rebecca Abstract: Chemical, biochemical and catalytic processes occur in environments where the specifics of structure, molecular reactivity and chemical properties are often very different than in an isolated gas phase environment. It is therefore important to have good predictive models that include the solution environment. Continuum models can in principle handle the majority of the bulk effects that depend on ion screening (dielectric constant). In contrast, the “non-electrostatic” or short-range interactions, such as hydrogen bonding or charge transfer, are not accounted for in the continuum model, and various strategies to include these effects are available. One such strategy is the continuum-cluster methodology, which is an implicit-explicit approach, whereby a small number of explicit solvent molecules are included to capture the short-range interactions and the resultant cluster is treated with a continuum model to capture the long-range or bulk energetics. This thesis work focuses on elucidating a strategy to systematize the number and placement of the explicit solvent molecules included in the cluster for modeling solution phase properties, in particular, dissociation constants. A new model, the Defined-Sector Explicit Solvent in Continuum Cluster Model (DSES-CC), provides a systematic basis for the inclusion of explicit solvation within the continuum model ansatz, resulting in a transferable explicit solvent arrangement for all systems containing a carboxylic or carboxylate moiety. The DSES-CC model achieves benchmark accuracy for prediction of first and second dissociation constants (pKa1 and pKa2 values) of carboxylic acids. Explicit solvation is shown to be essential for accurate prediction of dissociation constants particularly due to the sensitivity of the property to small changes in free energy of dissociation. All calculations carried out in the development and implementation of DSES-CC have been done with COSab, the locally modified version of the COSMO in GAMESS software package. Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-164314 Dissertation Published Version Originally published at: Abramson, Rebecca. Solvent effects in quantum chemical-based methods : I. defined-sector explicit sol- vent in the continuum model approach for computational prediction of PKa and II. algorithmic strategies towards inclusion of first solvation shell effects. 2013, University of Zurich, Faculty of Science. Solvent Effects in Quantum Chemical-based Methods: I. Defined-sector Explicit Solvent in the Continuum Model Approach for Computational Prediction of pKa and II. Algorithmic Strategies Towards Inclusion of First Solvation Shell Effects. Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Rebecca Abramson aus Australien Promotionskomitee Prof. Dr. Kim Baldridge (Vorsitz) Prof. Dr. Jay Siegel Prof. Dr. Amedeo Caflisch Zürich, 2013 ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! Copyright © 2013 Rebecca Abramson All rights reserved ! ii Acknowledgements I first met my research advisor, Kim Baldridge, in January 2005, after completing only one year of my Bachelors’ degree. This one-month internship sparked what has now been a nine-year relationship, culminating in this thesis work. I cannot imagine a more dedicated and motivational advisor than Kim, and I am so thankful for the interest, advice and support she has shown towards my professional development, both scientifically and personally. I am also thankful to Jay Siegel for the many interesting discussions and insights. Having had a connection with the University of Zürich now since 2005, I have crossed paths with so many wonderful people. In particular, I’d like to mention Anne Bowen, Celine Amoreira and Yohann Potier, who immediately welcomed me and patiently taught me GAMESS, Laura Berstis, who has been a constant source of inspiration, Mike Packard, whose patience with all things computer/grid related is highly admirable and greatly appreciated and Fitore Kasumaj; all of whom became close friends. I am also thankful for the friendships with so many other members of the ‘old crew’; Derik Frantz, Roman Maag, Silvia Rocha and Anna Butterfield. A particular thank you to Oliver Alleman and Jessica Clavadetscher for sharing this last year with me. All members of the Baldridge group have been a pleasure to work alongside. In addition to the members already mentioned, I’d like to thank Laura Zoppi, Heidi Weber, Tosaporn Sattasthuchana, Löic Roch, Timm Reuman, Limor Shenar Jackson and Roberto Peverati. I am most thankful to the Grid group (Sergio Maffioletti, Riccardo Murri, Mike Packard and Tyanko Aleksiev) for all the computational support. I am also extremely grateful for the fantastic administrative help offered by our secretarial staff in the OCI (Salomé Fässler, Sarah Amman and Marianne Grima). In particular, I thank Salomé Fässler for following my PhD process from the initial visa application, almost through to graduation, and becoming a very close friend with whom I shared many great moments along the way. ! iii I feel fortunate to have been part of the CMSZH graduate school and I’m very appreciative for the additional opportunities they have offered us. In addition to my friends from the university, I am most thankful to have made so many wonderful friends in Zürich. I feel particularly indebted to the families that have essentially adopted me over the years for the Shabbats and festivals; I thank the Braden-Golays, the Bessermanns and the Haymanns for feeding me and making me feel a part of their families. Thank you to my own parents for their boundless love, support and encouragement to pursue a career abroad. I cherish the trips to the UK, Israel, Italy, Stockholm, Paris and Barcelona that I’ve shared with my dad over the past years abroad. My sisters, whom I miss daily, I thank for the love, support and ginger cookies that crossed sees. I also thank my Aunt, Julie, for sending emergency supplies of Australian liquorice and other goodies, and for the wonderful times we spent together in New York and Paris. Finally I would like to thank Kim Baldridge, Jay Siegel, Joe O’Connor and Amedeo Caflisch, for acting as my Promotionskomittee. ! iv ABSTRACT ! Chemical, biochemical and catalytic processes occur in environments where the specifics of structure, molecular reactivity and chemical properties are often very different than in an isolated gas phase environment. It is therefore important to have good predictive models that include the solution environment. Continuum models can in principle handle the majority of the bulk effects that depend on ion screening (dielectric constant). In contrast, the “non-electrostatic” or short-range interactions, such as hydrogen bonding or charge transfer, are not accounted for in the continuum model, and various strategies to include these effects are available. One such strategy is the continuum-cluster methodology, which is an implicit-explicit approach, whereby a small number of explicit solvent molecules are included to capture the short-range interactions and the resultant cluster is treated with a continuum model to capture the long-range or bulk energetics. This thesis work focuses on elucidating a strategy to systematize the number and placement of the explicit solvent molecules included in the cluster for modeling solution phase properties, in particular, dissociation constants. A new model, the Defined-Sector Explicit Solvent in Continuum Cluster Model (DSES-CC), provides a systematic basis for the inclusion of explicit solvation within the continuum model ansatz, resulting in a transferable explicit solvent arrangement for all systems containing a carboxylic or carboxylate moiety. The DSES-CC model achieves benchmark accuracy for prediction of first and 1 2 second dissociation constants (pKa and pKa values) of carboxylic acids. Explicit solvation is shown to be essential for accurate prediction of dissociation constants particularly due to the sensitivity of the property to small changes in free energy of dissociation. All calculations carried out in the development and implementation of DSES-CC have been done with COSab, the locally modified version of the COSMO in GAMESS software package. While the derived DSES-CC model provides a rigorous means to include first solvation shell effects, optimal use of such ideas would involve an integrated approach, where any functionality could be treated without having to identify a new ! v DSES-CC for each functional group. In this work, the idea of a distance dependent dielectric function is investigated, where the distance function is dependent on the electron density of the solute system. A number of algorithmic steps towards this goal have been pursued in this work, including a) cavity construction components, b) outlying charge error correction schemes, and c) general efficiency of model algorithmic components. The basic cavity construction routine is enhanced to include a variety of vdW radii options, enabling greater