This dissertation is mainly focused on charge assisted noncovalent interactions specially hydrogen and halogen bonds. Generally, noncovalent interactions are only weak forces of interaction but an introduction of suitable charge on binding units increases the strength of the noncovalent bonds by a several orders of magnitude. These charge assisted noncovalent interactions have wide ranges of applications from crystal engineering to drug design. Not only that, nature accomplishes a number of important tasks using these interactions. Although, a good number of theoretical and experimental studies have already been done in this field, some fundamental properties of charge assisted hydrogen and halogen bonds still lack molecular level understanding and their electronic properties are yet to be explored. Better understanding of the electronic properties of these bonds will have applications on the rational design of drugs, noble functional materials, catalysts and so on. In most of this dissertation, comparative studies have been made between charge and neutral noncovalent interactions by quantum mechanical calculations. The comparisons are primarily focused on energetics and the electronic properties. In most of the cases, comparative studies are also made between hydrogen and halogen bonds which contradict the long time notion that the H-bond is the strongest noncovalent interactions.Besides that, this dissertation also explores the long range behavior and directional properties of various neutral and charge assisted noncovalent bonds.

Protein folding studies have provided important insights about the key role of non-covalent interactions in protein structure and conformational stability. Some of these interactions include salt bridges, cation-π, and anion-Ï€ interactions. Understanding these interactions is crucial to developing methods for predicting protein secondary, tertiary, quaternary structure from primary sequence and understanding protein-protein interactions and protein-ligand interactions. Several studies have described how the interaction between two amino acid side chains have a substantial effect on protein structure and conformational stability. This is under the assumption that the interaction between the two amino acids is independent of surrounding interactions. We are interested in understanding how salt bridges, cation-π, and anion-π interactions affect each other when they are in close proximity. Chapter 1 is a brief introduction on noncovalent interactions and noncovalent interaction cooperativity. Chapter 2 describes the progress we have made measuring the cooperativity between noncovalent interactions involving cations, anions and aromatic amino acids in a coiled-coil alpha helix model protein. Chapter 3 describes cooperativity between cation, anion, and nonaromatic hydrophobic amino acids in the context of a coiled-coil alpha helix. In chapter 4 we describe a strong anion-π interaction in a reverse turn that stabilizes a beta sheet model protein. In chapter 5 we measure the interaction between a cysteine linked maleimide and two lysines in a helix and show that it is a general strategy to stabilize helical structure.

Bio-inspired monomers functionalized with nucleobase or ionic group allowed synthesis of supramolecular polymers using free radical polymerization and controlled radical polymerization techniques. Comprehensive investigations for the structure-property-morphology relationships of these supramolecular polymers elucidated the effect of noncovalent interactions on polymer physical properties and self-assembly behaviors. Reverse addition-fragmentation chain transfer (RAFT) polymerization afforded acrylic ABC and ABA triblock copolymers with nucleobase-functionalized external blocks and a low-Tg central block. The hard-soft-hard triblock polymer architecture drove microphase-separation into a physically crosslinked hard phase in a low Tg matrix. Hydrogen bonding in the hard phase enhanced the mechanical strength and maintained processability of microphase-separated copolymers for thermoplastics and elastomers. A thermodynamically favored one-to-one stoichiometry of adenine and thymine yielded the optimal thermomechanical performance. Intermolecular hydrogen bonding of two thymine units and one adenine unit allowed the formation of base triplets and directed self-assembly of ABC triblock copolymers into remarkably well-defined lamellae with long-range ordering. Acetyl protected cytosine and guanine-containing random copolymers exhibited tunable cohesive strength and peel strength as pressure sensitive adhesives. Post-functionalization converted unprotected cytosine pendent groups in acrylic random copolymers to ureido-cytosine units that formed quadruple self-hydrogen bonding. Ureido-cytosine containing random copolymers self-assembled into nano-fibrillar hard domains in a soft acrylic matrix, and exhibited enhanced cohesive strength, wide service temperature window, and low moisture uptake as soft adhesives. A library of styrenic DABCO salt-containing monomers allowed the synthesis of random ionomers with two quaternized nitrogen cations on each ionic pendant group. Thermomechanical, morphological, and rheological analyses revealed that doubly-charged DABCO salts formed stronger ionic association and promoted more well-defined microphase-separation compared to singly-charged analogs with the same charge density. Bulkier counterions led to enhanced thermal stability, increased phase-mixing, and reduced water uptake for DABCO salt-containing copolymers, while alkyl substituent lengths only significantly affected water uptake of DABCO salt-containing copolymers. Step growth polymerization of plant oil-based AB monomer and diamines enabled the synthesis of unprecedented isocyanate-free poly(amide hydroxyurethane)s, the first examples of film-forming, linear isocyanate-free polyurethanes with mechanical integrity and processability. Successful electrospinning of segmented PAHUs afforded randomly orientated, semicrystalline fibers that formed stretchable, free-standing fiber mats with superior cell adhesion and biocompatibility. / Ph. D.

Molecular modelling has become a well-established tool for studying biological mole- cules, moreover with the prospect of being useful for drug development. The thesis summarises research on the methodological advances in the treatment of molecular flexibility and intermolecular interactions. Altogether, seven original publications are accompanied by a text which aims to provide a general introduction to the topic as well as to emphasise some consequences of the computer-aided drug design. The molecular flexibility is tackled by a study of a drug-DNA interaction and also by an investigation of small drug molecules in the context of implicit solvent models. The approaches which neglect the conformational freedom are probed and compared with experiment in order to suggest later, how to cope with such a freedom if in- evitable. The noncovalent interactions involving halogen atoms and their importance for drug development are briefly introduced. Finally, a model for a faithful description of halogen bonds in the framework of molecular mechanics is developed and its per- formance and limits are tested by a comparison with benchmark ab initio calculations and experimental data. 1

Noncovalent interactions are vital for functioning of biological systems. For instance, they facilitate DNA base pairing or protein folding. Recently, in addition to classical noncovalent interactions such as hydrogen bond, nonclassical noncovalent interactions have been discovered. An example of these interactions is halogen bond belonging to the class of σ-hole interactions, the knowledge of which is already being useful for medical compound design. The aim of this work is to find out if the chalcogen bond, also a σ-hole interaction, plays a role in the binding of existing viral inhibitors, too. Following that, we are also interested whether or to what extent can these existing chalcogen bonds be optimized for a greater affinity of the inhibitor binding. Several protein-ligand crystal structures exhibiting geometrical properties favoring a chalcogen bond have been found in the PDB database. We examined the interaction energies and the interaction energy geometrical dependencies of model systems derived from these crystal structures by means of quantum chemical calculations. Further we have optimized their strength by a series of substitutions. We thus propose that chalcogen bond can become a player in rational design of inhibitors of viral enzymes and their protein target. Keywords: Noncovalent...

Noncovalent interactions are involved in many biological processes in which biomolecules bind specifically and reversibly to a partner. Often, proteins do not have a biological activity without the presence of a partner, a ligand. Biological signals are produced when proteins interact with other proteins, peptides, oligonucleotides, nucleic acids, lipids, metal ions, polysaccharides or small organic molecules. Some key steps in the drug discovery process are based on noncovalent interactions. We have focused our research on the steps involving ligand screening, competitive binding and ‘off-target’ binding. The first paper in this thesis investigated the complicated electrospray ionization process with regards to noncovalent complexes. We have proposed a model that may explain how the equilibrium between a protein and ligand changes during the droplet evaporation/ionization process. The second paper describes an evaluation of an automated chip-based nano-ESI platform for ligand screening. The technique was compared with a previously reported method based on nuclear magnetic resonance (NMR), and excellent correlation was obtained between the results obtained with the two methods. As a general conclusion we believe that the automated nano-ESI/MS should have a great potential to serve as a complementary screening method to conventional HTS. Alternatively, it could be used as a first screening method in an early phase of drug development programs when only small amounts of purified targets are available. In the third article, the advantage of using on-line microdialysis as a tool for enhanced resolution and sensitivity during detection of noncovalent interactions and competitive binding studies by ESI-MS was demonstrated. The microdialysis device was improved and a new approach for competitive binding studies was developed. The last article in the thesis reports studies of noncovalent interactions by means of nanoelectrospray ionization mass spectrometry (nanoESI-MS) for determination of the specific binding of selected drug candidates to HSA. Two drug candidates and two known binders to HSA were analyzed using a competitive approach. The drugs were incubated with the target protein followed by addition of site-specific probes, one at a time. The drug candidates showed predominant affinity to site I (warfarin site). Naproxen and glyburide showed affinity to both sites I and II. / QC 20100705

Noncovalent interactions are of great importance in studies on crystal design and drug discovery. One such noncovalent interaction, halogen bonding, is present between a covalently bound halogen atom and a Lewis base. A halogen bond is a directional interaction caused by the anisotropic distribution of charge on a halogen atom X covalently bound to A, which in turn forms a positive region called σ-hole on the A–X axis. Utilization of halogen bonds in lead optimization have been rarely considered in drug discovery until recently and yet more than 50% of the drug candidates are halogenated. To date, the halogen bond has not been subjected to practical molecular mechanical-molecular dynamics (MM-MD) study, where this noncovalent interaction cannot be described by conventional force fields because they do not account for the anisotropic distribution of the charge density on the halogen atoms. This problem was solved by the author and, for the first time, an extra-point of positive charge was used to represent the σ-hole on the halogen atom. This approach is called positive extra-point (PEP) approach. Interestingly, it was found that the performance of the PEP approach in describing halogen bond was better than the semiempirical methods including the recent halogen-bond corrected PM6 (PM6-DH2X) method. The PEP approach also gave promising results in describing other noncovalent halogen interactions, such as C–X···H and C–X···π-systems. The PEP resulted in an improvement in the accuracy of the electrostatic-potential derived charges of halogen-containing molecules, giving in turn better dipole moments and solvation free energies compared to high-level quantum mechanical and experimental data.With the aid of our PEP approach, the first MM-molecular dynamics (MM-MD) study of inhibitors that form a halogen bond with a receptor was performed for tetrahalobenzotriazole inhibitors complexed to cyclin-dependent protein kinase (CDK2). When the PEP approach was used, the calculated MM-generalized Born surface area (MM-GBSA)//MM-MD binding energies for halobenzimidazole and halobenzotriazole inhibitors complexed with protein kinase CK2 were found to correlate well with the corresponding experimental data, with correlation coefficients R2 of greater than 0.90. The nature and strength of halogen bonding in halo molecule···Lewis base complexes were studied in terms of molecular mechanics using our PEP approach. The contributions of the σ-hole (i.e., positively charged extra-point) and the halogen atom to the strength of this noncovalent interaction were clarified using the atomic parameter contribution to the molecular interaction approach. The molecular mechanical results revealed that the halogen bond is electrostatic and van der Waals in nature. The strength of the halogen bond increases with increasing the magnitude of the extra-point charge. The van der Waals interaction’s contribution to the halogen bond strength is most favorable in chloro complexes, whereas the electrostatic interaction is dominant in iodo complexes.The failure of the PM6 semiempirical method in describing noncovalent halogen interactions —not only halogen bonds, but also hydrogen bonds involving halogen atoms— was reported and corrected by the introduction of a second and third generation of noncovalent halogen interactions correction. The developed correction yielded promising results for the four examined noncovalent halogen interactions, namely: C–X···O, C–X···N, C–X···π-system, and C–X···H interactions.

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