Peptides have assumed considerable importance in pharmaceutical industry and vaccine research. Understanding the structural features of these peptide molecules can be effective not only in mimicking natural proteins but also in the design of new biomaterials. Polypeptide sequences consisting of twenty genetically coded amino acids possess structural flexibility, which makes the predictions difficult. However, the introduction of non-protein amino acids into the peptide chain restricts the available range of backbone conformations and acts as stereochemical directors of polypeptide chain folding. Such conformationally rigid residues allow the formation of well defined structures like helices, strands etc, which further assemble into super secondary structural motifs by flexible linkages. Crystal structure determination of the oligopeptides by X-ray diffraction gives insight into the specific conformational states, modes of aggregation, hydrogen bond interactions, solvation of peptides and various weakly polar interactions involving the side chains of aromatic residues (Phe, Trp and Tyr). In β-, γ- and higher ω-amino acids, due to the insertion of one or more methylene groups between the N- and Cα-atoms into the peptide backbone the accessible conformational space is greater than the α-amino acids. The β-, γ-, δ-…. amino acid residues belong to the family of ω-amino acids. Extensive research in the field of β-peptides, which have been experimentally verified or theoretically postulated, has assigned several helices, turns and sheets. The use of ω-amino acid residues in conjunction with α-residues permits systematic exploration of the effects of introducing additional backbone atoms into well-characterized α-peptide structures. The observation of new families of hydrogen bonded motifs in the hybrid peptides containing α- and ω-amino acids are the recent interest in this regard. This thesis reports results of X-ray crystallographic studies of eighteen designed peptides and four protected ω-amino acids listed below. Within brackets are given the abbreviations used for the sequences (Symbol U represents Aib). The ω-amino acids reported in this thesis are: (S)-β3-HAla (β3-homoalanine), (R)-β3-HVal, (S)-β3-HVal (β3-homovaline), (S)-β3-HPhe (β3-homophenylalanine), (S)-β3-HPro (β3-homoproline), βGly (β-homoglycine), γAbu (gamma aminobutyric acid) and δAva (delta aminovaleric acid). 1. Boc-Leu-Trp-Val-OMe (LWV), C28H42N4O6 2. Ac-Leu-Trp-Val-OMe (Space group P21) (LWV1), C25H36N4O5 3. Ac-Leu-Trp-Val-OMe (Space group P212121) (LWV2), C25H36N4O5 4. Boc-Leu-Phe-Val-OMe (LFV), C26H41N3O6 5. Ac-Leu-Phe-Val-OMe (LFV1), C23H35N3O5 6. Boc-Ala-Aib-Leu-Trp-Val-OMe (AULWV), C35H54N6O8 7. Boc-Trp-Trp-OMe (WW), C28H32N4O5 8. Boc-Trp-Aib-Gly-Trp-OMe. (WUGW), C34H42N6O7 9. Boc-Leu-Trp-Val-Ala-Aib-Leu-Trp-Val-OMe (H8AU), C57H84N10O11 10. Boc-(S)-β3-HAla-NHMe (BANH), C10H20N2O3 11. Boc-(R)-β3-HVal-NHMe (BVNH), C12H24N2O3 12. Boc-(S)-β3-HPhe-NHMe (BFNH), C16H24N2O3 13. Boc-(R)-β3-HVal-(R)-β3-HVal-OMe (BVBV), C18H34N2O5 14. Boc-(R)-β3-HVal-(S)-β3-HVal-OMe (LVDV), C18H34N2O5 15. Boc-(S)-β3-HPro-OH (BPOH), C11H19N1O4 16. Boc-Leu-Phe-Val-Aib-(S)-β3-HPhe-Leu-Phe-Val-OMe (UBF8), C60H88N8O11 17. Piv-Pro-Gly-NHMe (PA1), C13H23N3O3 18. Piv-Pro-βGly-NHMe (PB1), C14H25N3O3 19. Piv-Pro-βGly-OMe (PBO), C14H24N2O4 20. Piv-Pro-δAva-OMe (PDAVA), C16H28N2O4 21. Boc-Pro-γAbu-OH (BGABU), C14H24N2O5 22. Boc-Aib-γAbu-OH (UG), C13H24N2O5 23. Boc-Aib-γAbu-Aib-OMe (UGU), C18H33N3O6 The thesis is divided into seven chapters. Chapter 1 gives a general introduction to the stereochemistry of polypeptide chains and the secondary structure classification: helices, β-sheets and β-turns followed by an overview of different types of weakly polar interactions involving the side chains of aromatic amino acid residues. This section also provides a brief overview of the conformational analysis of β-, γ- and higher ω-amino acid residues in oligomeric β-peptides and in α,ω-hybrid peptides. A brief discussion on X-ray diffraction and solution to the phase problem is also presented. Chapter 2 describes the crystal structures of the peptides, Boc-Leu-Trp-Val-OMe (LWV), the two polymorphs of Ac-Leu-Trp-Val-OMe (LWV1 and LWV2), Boc-Leu-Phe-Val-OMe (LFV), Ac-Leu-Phe-Val-OMe (LFV1) and Boc-Ala-Aib-Leu-Trp-Val-OMe (AULWV), in order to explore the nature of interactions between aromatic rings, specifically the indole side chain of Trp residues [1]. Peptide LWV adopts a type I β-turn conformation, stabilized by an intramolecular 4→1 hydrogen bond. Molecules of LWV pack into helical columns stabilized by two intermolecular hydrogen bonds, Leu(1)NH…O=CTrp(2) and Indole NH…O=CLeu(1). The superhelical columns further pack into the tetragonal space group P43 by means of a continuous network of indole - indole interactions. The peptide Ac-Leu-Trp-Val-OMe crystallized in two polymorphic forms: P21 (LWV1) and P212121 (LWV2). In both forms, the peptide backbone is extended and the crystal packing shows anti-parallel β-sheet arrangement. Similarly, extended strand conformation and anti-parallel β-sheet formation are also observed in the Phe containing analogs, LFV and LFV1. The pentapeptide AULWV adopts a short stretch of 310-helix. Analysis of aromatic - aromatic and aromatic - amide interactions in the structures of peptides LWV, LWV1 and LWV2 are reported along with the examples of 12 Trp containing peptides from the Cambridge Structural Database. The results suggest that there is no dramatic preference for the orientation of two proximal indole rings. In Trp containing peptides specific orientations of the indole ring, with respect to the preceding and succeeding peptide units, appear to be preferred in β-turns and extended structures. Crystal parameters LWV: C28H42N4O6; P43; a = 14.698(1) Å, b = 14.698(1) Å, c = 13.975(2) Å; Z = 4; R = 0.0737, wR2 = 0.1641. LWV1: C25H36N4O5; P21; a =10.966(3) Å, b = 9.509(2) Å; c = 14.130(3) Å, β = 104.94(1)°; Z = 2; R = 0.0650, wR2 = 0.1821. LWV2: C25H36N4O5; P212121; a = 9.533(6) Å, b = 14.148(9) Å, c = 19.53(1) Å, Z = 4; R = 0.0480, wR2 = 0.1365. LFV: C26H41N3O6; C2; a = 31.318(8) Å, b = 10.022(3) Å, c = 9.657(3) Å, β = 107.41(1)°; Z = 4; R = 0.0536, wR2 = 0.1328. LFV1: C23H35N3O5; P212121; a = 9.514(8) Å, b = 13.56(1) Å, c = 20.04(2) Å, Z = 4; R = 0.0897, wR2 = 0.1960. AULWV: C35H54N6O8.2H2O; P21; a = 9.743(3) Å, b = 22.807(7) Å, c = 10.106(3) Å, β = 105.73(2)°; Z = 2; R = 0.0850; wR2 = 0.2061. Chapter 3 describes the crystal structures of three peptides containing Trp residues at both N- and C-termini of the peptide backbone: Boc-Trp-Trp-OMe (WW), Boc-Trp-Aib-Gly-Trp-OMe (WUGW) and Boc-Leu-Trp-Val-Ala-Aib-Leu-Trp-Val-OMe (H8AU). Peptide WW adopts an extended conformation and the molecules pack into an arrangement of parallel β-sheet in crystals, stabilized by three intermolecular N-H…O hydrogen bonds. The potential hydrogen bonding group NE1H of Trp(1), which does not take part in hydrogen bonding interaction with an oxygen acceptor participate in an intermolecular N-H…π interaction. Peptide WUGW adopts a folded structure, stabilized by a consecutive type II-I’ β-turn conformation. The crystal of WUGW contains a stoichiometric amount of chloroform in two distinct sites each with an occupancy factor of 0.5 and the structure provides examples of N-H…π, C-H…π, π…π, N-H…Cl, C-H…Cl and C-H…O interactions [2]. The molecular conformation of H8AU reveals a 310-helix. The crystal structure of H8AU reveals an interesting packing motif in which helical columns are stabilized by side chain - backbone hydrogen bond involving the indole NH of Trp(2) as donor and C=O group of Leu(6) as acceptor of a neighboring molecule, which closely resembles the hydrogen bonding pattern obtained in the tripeptide LWV [1]. Helical columns also associate laterally and strong interactions are observed between the Trp(2) and Trp(7) residues on neighboring molecules [3]. The edge-to-face aromatic interactions between the indoles suggest a potential C-H…π interaction involving the CE3H of Trp (2) Crystal parameters WW: C28H32N4O5; P212121; a = 5.146(1) Å, b = 14.039(2) Å, c = 35.960(5) Å; Z = 4; R = 0.0503, wR2 = 0.1243. WUGW: C34H42N6O7.CHCl3; P21; a = 12.951(5) Å, b = 11.368(4) Å, c = 14.800(5) Å, β = 101.41(2)°; Z = 2; R = 0.1095, wR2 = 0.2706. H8AU: C57H84N10O11; P1; a = 10.494(7) Å, b = 11.989(7) Å, c = 13.834(9) Å, α = 70.10(1)°, β = 82.74(1)°, γ = 78.96(1)°; Z = 1; R = 0.0855, wR2 = 0.1965. Chapter 4 describes the crystal structures of four protected β-amino acid residues, Boc-(S)-β3-HAla-NHMe (BANH); Boc-(R)-β3-HVal-NHMe (BVNH); Boc-(S)-β3-HPhe-NHMe (BFNH); Boc-(S)-β3-HPro-OH (BPOH) and two β-dipeptides, Boc-(R)-β3-HVal-(R)-β3-HVal-OMe (BVBV); Boc-(R)-β3-HVal-(S)-β3-HVal-OMe (LVDV). Gauche conformations about the Cβ-Cα bonds (θ ~ ± 60°) are observed for the β3-HPhe residue in BFNH and all four β3-HVal residues in the dipeptides BVBV and LVDV. Trans conformations (θ ~ 180°) are observed for β3-HAla residues in both independent molecules in BANH and for the β3-HVal and β3-HPro residues in BVNH and BPOH, respectively. In all these cases except for BPOH, molecules associate in the crystals via intermolecular backbone hydrogen bonds leading to the formation of sheets. The polar strands formed by β3-residues aggregate in both parallel (BANH, BFNH, LVDV) and anti-parallel (BVNH, BVBV) fashion. Sheet formation accommodates both the trans and gauche conformations about the Cβ - Cα bonds [4]. Crystal parameters BANH: C10H20N2O3; P1; a = 5.104(2) Å, b = 9.469(3) Å, c = 13.780(4) Å, α = 80.14(1)°, β = 86.04(1)°, γ = 89.93(1)°; Z =2; R = 0.0489, wR2 = 0.1347. BVNH: C12H24N2O3; P212121; a = 8.730(2) Å, b = 9.741(3) Å, c = 17.509(5) Å; Z = 4; R = 0.0479, wR2 = 0.1301. BFNH: C16H24N2O3; C2; a = 20.54(1) Å, b = 5.165(3) Å, c = 16.87(1) Å, β = 109.82(1)°; Z = 4; R = 0.0909, wR2 = 0.1912. BVBV: C18H34N2O5; P212121; a = 9.385(2) Å, b = 11.899(2) Å, c = 19.199(4) Å; Z = 4; R = 0.0583, wR2 = 0.1589. LVDV: C18H34N2O5; P212121; a = 5.170(4) Å, b = 10.860(8) Å, c = 37.30(3) Å; Z = 4; R = 0.0787, wR2 = 0.1588. BPOH: C11H19N1O4; P1; a = 5.989(2) Å, b = 6.651(2) Å, c = 8.661(3) Å, α = 70.75(1)°, β = 77.42(1)°, γ = 86.98(1)°; Z = 1; R = 0.0562, wR2 = 0.1605. Chapter 5 describes a new class of polypeptide helices in hybrid sequences containing α-, β- and γ-residues. The molecular conformation in crystals determined for the octapeptide Boc-Leu-Phe-Val-Aib-(S)-β3-HPhe-Leu-Phe-Val-OMe (UBF8) reveals an expanded helical turn in the hybrid sequence (ααβ)n. A repetitive helical structure composed of C14 hydrogen bonded units is observed. Using experimentally determined backbone torsion angles for the hydrogen bonded units formed by hybrid sequences, the energetically favorable hybrid helices have been generated. Conformational parameters are provided for C11, C12, C13, C14 and C15 helices in hybrid sequences [5]. Crystal parameters UBF8: C60H88N8O11; P212121; a = 12.365(1) Å, b = 18.940(2) Å, c = 27.123(3) Å; Z = 4; R = 0.0625, wR2 = 0.1274. Chapter 6 describes the crystal structures of five model peptides Piv-Pro-Gly-NHMe (PA1), Piv-Pro-βGly-NHMe (PB1), Piv-Pro-βGly-OMe (PBO), Piv-Pro-δAva-OMe (PDAVA) and Boc-Pro-γAbu-OH (BGABU). A comparison of the structures of peptides PA1 and PB1 illustrates the dramatic consequences upon backbone homologation in short sequences. The molecule PA1 adopts a type II β-turn conformation in the crystal state, while in PB1, the molecule adopts an open conformation with the β-residue being fully extended. The peptide PBO, which differs from PB1 by replacement of the C-terminal NH group by an O-atom, adopts an almost identical molecular conformation and packing arrangement in the crystal state. In peptide PDAVA, the observed conformation resembles that determined for PB1 and PBO, with the δAva residue being fully extended. In peptide BGABU, the molecule undergoes a chain reversal, revealing a β-turn mimetic structure stabilized by a C-H…O hydrogen bond [6]. Crystal parameters PA1: C13H23N3O3; P1; a = 5.843(1) Å, b = 7.966(2) Å, c = 9.173(2) Å, α = 114.83(1)°, β = 97.04(1)°, γ = 99.45(1)°; Z = 1; R = 0.0365, wR2 = 0.0979. PB1: C14H25N3O3.H2O; P212121; a = 6.297(3) Å, b = 11.589(5) Å, c = 22.503(9) Å; Z = 4; R = 0.0439, wR2 = 0.1211. PBO: C14H24N2O4.H2O; P212121; a = 6.157(2) Å, b = 11.547(4) Å, c = 23.408(8) Å; Z = 4; R = 0.050, wR2 = 0.1379. PDAVA: C16H28N2O4.H2O; P21212; a = 11.33(1) Å, b = 25.56(2) Å, c = 6.243(6) Å; Z = 4; R = 0.0919, wR2 = 0.2344. BGABU: C14H24N2O5; P61; a = 9.759(2) Å, b = 9.759(2) Å, c = 29.16(1) Å; Z = 6; R = 0.0773, wR2 = 0.1243. Chapter 7 describes the crystal structures of a dipeptide, Boc-Aib-γAbu-OH (UG) and a tripeptide, Boc-Aib-γAbu-Aib-OMe (UGU) containing a single γAbu residue in each sequence. The structure of UG forms a reverse turn stabilized by a 10-membered intramolecular C-H…O hydrogen bonded ring. The peptide UGU crystallized in the triclinic space group P⎯1 with two molecules in the asymmetric unit resulting in a parallel assembly of sheets in crystals. Notably, the insertion of a single Aib residue at the C-terminus drastically changes the overall conformation of the structures. Crystal parameters UG: C13H24N2O5; P21/c; a = 16.749(3) Å, b = 5.825(1) Å, c = 16.975(3) Å; β = 111.82(1); Z = 4; R = 0.0507; wR2 = 0.1294. UGU: C18H33N3O6; P⎯1; a = 9.576(6) Å, b = 13.98(1) Å, c = 17.83(1); α = 85.31 (1); β = 77.46 (1); γ = 71.39 (1); Z = 4; R = 0.0648; wR2 = 0.1837.

Structural studies of peptides are of great importance in developing novel and effective biomaterials ranging from drugs and vaccines to nano materials with industrial applications. In addition, they provide model systems to study and mimic the protein conformations. The ability to generate folded intramolecularly hydrogen bonded structures in short peptides is essential for peptide design strategies, which rely on the use of folding nuclei in the construction of secondary structure modules like helices and β-hairpins. In these approaches, conformational choices at selected positions are biased, using local stereochemical constraints, that limit the range of accessible backbone torsion angles. X-ray crystallographic studies of designed peptides provide definitive proof of the success of a design strategy, and provide essential structural information that can be utilized in the future design of biologically and structurally important polypeptides. Recent trends in peptide research focus on the incorporation of β-, γ- and higher homologs of the α-amino acid residues in designed peptides as they confer more proteolytic stability to the polypeptides. X-ray crystallographic studies of such modified peptides containing non-protein residues are essential, since information on the geometric and stereochemical properties of modified amino acids can only be gathered from the systematic structural studies of synthetic peptides incorporating them. This thesis reports a systematic study of the structures and conformations of amino acid derivatives and designed peptides containing stereochemically constrained α-, β- and γ-amino acid residues and the structural studies of polymorphic peptide helices. The structures described in thesis contain the Cα,α-dialkyalted α-residues α-aminoisobutyric acid (Aib) and 1-aminocyclohexane-1-carboxylic acid (Ac6c), the β-amino acid residue 1-aminocyclohexane acetic acid (β3,3Ac6c) and the γ-amino acid residue 1-aminomethylcyclohexaneacetic acid (gabapentin, Gpn). The crystal structure determination of peptides incorporating conformationally constrained α-, β- and γ- amino acid residues permitted the characterization of new types of hydrogen bonded turns and polymorphs. The studies enabled the precise determination of conformational and geometric parameters of two ω-amino acid residues, gabapentin and β 3,3Ac6c and provided detailed information about the conformational excursions possible for peptide molecules. This thesis is divided into 10 chapters. Chapter 1 gives a general introduction to the stereochemistry of the polypeptide chain, description of backbone torsion angles of α- and ω- amino acid residues and the major secondary structures of α-peptides, β-peptides, γ-peptides and hybrid peptides. A brief introduction to polymorphism and weak interactions, in particular aromatic interactions, is also provided, followed by a discussion on X-ray diffraction and solution to the phase problem. Chapter 2 describes the crystal structures of gabapentin zwitterion and its eight derivatives (Ananda, Aravinda, Vasudev et al., 2003). The crystal structure of the gabapentin zwitterions determined in this study is identical to that previously reported (Ibers, J. A. Acta Crystallogr. 2001, C57, 641-643). Eight of the nine achiral compounds crystallized in centrosymmetric space groups P21/c, C2/c or Pbca, while one derivative (Tos-Gpn-OH) crystallized in non-centrosymmetric space group Pna21 with four independent molecules in the asymmetric unit.The structural studies presented in this chapter reveal that the geminal substituents on the Cβ atom limits the values of dihedral angles θ1 and θ2 to ±60°, resulting in folded backbone conformations in all the examples. Intramolecular hydrogen bonds with 7-atoms in the hydrogen bond turn (C7) are observed in three derivatives, gabapentin hydrochloride (GPNCL), Boc-Gpn-OH (BGPNH) and Piv-Gpn-OH (PIVGPN), while a 9-atom hydrogen bonded turn (C9) is observed in Ac-Gpn-OH (ACGPH). Unique structural features, such as an unusual anti conformation of the COOH group (in ACGPH) and positional disorder of the cyclohexane ring (in BGPNN), indicating the co-existence of both the interconvertible chair conformations, are revealed by the crystal structure analyses. Chapter 3 describes the structural characterization of novel hydrogen bonded conformations of homo oligomers of Gpn. The crystal structures of three peptides, Boc-Gpn-Gpn-NHMe (GPN2), Boc-Gpn-Gpn-Leu-OMe (GPN2L) and Boc-Gpn-Gpn-Gpn-Gpn-NHMe (GPN4) provide the first crystallographic characterization of two new families of polypeptide structures, the C9 helices and C9 ribbons (Vasudev et al., 2005, 2007), in which the molecular conformations are stabilized by contiguous C9 turns formed by the hydrogen bonding between the CO group of residue (i) and the NH group of residue (i+2). The C9 hydrogen bond is characterized by a specific combination of the four torsion angles for the Gpn backbone, with the torsion angles θ1 and θ2 adopting g+/g+ or g /g- conformations. The structural analysis also permits precise determination of hydrogen bond geometry for the C9 structures, which is highly linear in contrast to the analogous γ-turn hydrogen bonds in α-peptides. A comparison of the backbone conformations in the three peptides reveals two classes of C9 hydrogen bonded secondary structures, namely C9 helices and C9 ribbons. The packing arrangement in these γ-peptides follows the same patterns as the helix packing in crystals of α-peptides. Chapter 4 describes ten crystal structures of short hybrid peptides containing the Gpn residue (Vasudev et al., 2007). In addition to the C7 and C9 hydrogen bonded turns which are defined by the backbone conformations at the Gpn residue, hybrid turns defined by a combination of backbone conformations at the α and γ-residues or at the β and γ-residues have been determined. Peptides Boc-Ac6c-Gpn-OH (ACGPH), Piv-Pro-Gpn-Val-OMe (PPGPV) and Boc-Val-Pro-Gpn-OH (VPGPH) reveal molecular conformation stabilized by intramolecular C9 hydrogen bonds, while Boc-Ac6c-Gpn-OMe (ACGPO) and Boc-Gpn-Aib-OH (GPUH) are stabilized by a C7 hydrogen bonded turn at the Gpn residue. An αγ hybrid turn with 12 atoms in the intramolecular hydrogen bonded rings (C12 turns) has been observed in the tripeptide Boc-Ac6c-Gpn-Ac6c-OMe (ACGP3), while βγ hybrid turns with 13 atoms in the hydrogen bonded ring (C13 turns) have been characterized in the tripeptides Boc-βLeu-Gpn-Val-OMe (BLGPV) and Boc- βPhe-Gpn-Phe-OMe (BFGPF). The two βγ C13 turns belong to two different categories and are characterized by different sets of backbone torsion angles for the β and γ residues. A γα C10 hydrogen bond, which is formed in the N→C direction (NHi ••• COi+2), as opposed to the regular hydrogen bonded helices of α-peptides, has also been observed in BFGPF. The Chapter provides a comparison of the backbone torsion angles of the Gpn residue in various hydrogen bonded turns and a brief comparison of the observed hydrogen bonded turns with those of the α-peptides. Chapter 5 describes the crystal structures of three αγ hybrid peptides which show C12/C10 mixed hydrogen bond patterns (Vasudev et al., 2007, 2008a; Chatterjee, Vasudev et al.,2008a). The insertion of gabapentin in the predominantly α-amino acid sequences in Boc-Ala-Aib-Gpn-Aib-Ala-OMe (AUGP5) and Boc-Leu-Gpn-Aib-Leu-Gpn-Aib-OMe results in the observation of helices stabilized by αα C10 (310-turn) and αγ C12 turns. The tetrapeptide Boc-Leu-Gpn-Leu-Aib-OMe reveals a novel conformation, stabilized by C12 (αγ) and C10 (γα) hydrogen bonds of opposite hydrogen bond directionalities. The conformations observed in crystals have been extended to generate C12 helix and C12/C10 helix with alternating hydrogen bond polarities in ( αγ)n sequences. The structure determination of three crystals, providing five molecular conformations, presented in this chapter provides the first crystallographic characterization of two types of helices predicted for the regular αγ hybrid peptides from theoretical calculations. The crystal structure of Boc-Ala-Aib-Gpn-Aib-Ala-OMe also provides an example for the co-existence of left-handed and right-handed helix in the asymmetric unit. Chapter 6 describes the structural studies of αγ hybrid peptides containing Aib and Gpn residues, and is divided into two parts. The first part presents the crystal structure analysis of peptides of sequence length 2 to 4, with alternating Aib and Gpn residues, and illustrates the conformational variability in αγ hybrid sequences as evidenced by the observation of conformational polymorphs (Chatterjee, Vasudev et al., 2008b; Vasudev et al., 2007; Ananda, Vasudev et al., 2005). The peptide Boc-Gpn-Aib-NHMe (GUN), Boc-Aib-Gpn-Aib-OMe (UGU), Boc-Gpn-Aib-Gpn-Aib-OMe (GU4O), Boc-Aib-Gpn-Aib-Gpn-OMe (UG4O) and Boc-Aib-Gpn-Aib-Gpn-NHMe (UG4N), all of which are potential candidates for exhibiting αγ C12 hydrogen bonds, reveal molecular conformations stabilized by diverse hydrogen bonded turns such as C7, C9, C12 and C17 in crystals. The conformational heterogeneity in this class of hybrid peptides is further evidenced by the observation of three polymorphs in the monoclinic space group P21/c for the tetrapeptide Boc-Aib-Gpn-Aib-Gpn-NHMe (UG4N), providing four independent peptide molecules adopting two distinct backbone conformations. In one polymorph, C12 helices terminated with an unusual three residue ( γαγ) C17 turn is observed, while the unfolding of helical conformation by solvent insertion into the backbone is observed in the other two polymorphs. The studies indicate the possible utility of Gpn residue in stabilizing locally folded conformations in the folding pathway, thus permitting their crystallographic characterization in multiple crystal forms. A discussion of the structural and conformational features of Gpn residues determined from all the crystal structures is presented in the Chapter, along with a φ-ψ plot for the Gpn residue. Part 2 of Chapter 6 describes the crystal structures of two octapeptides, Boc-Gpn-Aib-Gpn-Aib-Gpn-Aib-Gpn-Aib-OMe (GU8) and Boc-Leu-Phe-Val-Aib-Gpn-Leu-Phe-Val-OMe (LFVUG8), featuring C12 turns at the Aib-Gpn segments (Chatterjee, Vasudev et al., 2009). GU8 folds into a C12 helix flanked by C9 hydrogen bonds at both the termini, while LFVUG8 adopts β-hairpin conformation with a chain-reversing C12 turn at the central Aib-Gpn segment. A remarkable feature of the Aib-Gpn turn in the β-hairpin structure is the anti conformation about the Cβ-Cα (θ2) bond, which is the only example of a Gpn residue not adopting gauche conformation for both θ1 and θ2. The crystal structures of the two peptides, mimicking the two major secondary structural elements of α-peptides in hybrid polypeptides, permits a comparative study of the mode of molecular packing in crystals of α-peptides and hybrid peptides. The chapter also discusses theoretical calculations on αγ hybrid sequences, which reveal new types of C12 hydrogen bonded turns. Chapter 7 describes the crystal structures of conformationally biased tert-butyl derivatives of Gpn. The crystallographic characterization of the E (trans) and Z (cis) isomers of the residue,three protected derivatives and a tripeptide provides examples of C7 and C9 hydrogen bonded conformations, suggesting that the C7 and C9 hydrogen bonds can be formed by Gpn residues with both the chair conformations of the cyclohexane ring. Chapter 8 describes the systematic structural studies of the derivatives and peptides of the stereochemically constrained β- amino acid residue, β3,3Ac6c (Vasudev et al., 2008c). The backbone torsion angles φ and θ adopt gauche conformation in majority of the examples, owing to the presence of a cyclohexane ring on the Cβ atom. In contrast to Gpn, β3,3Ac6c does not show strong preference for adopting intramolecularly hydrogen bonded conformations. Of the 16 crystal structures determined, intramolecular hydrogen bonds involving the β-residue are observed only in 4 cases. The amino acid zwitterion (BAC6C), the hydrochloride (BACHCL) and the dipeptide Boc-β3,3Ac6c-β3,3Ac6c-NHMe (BAC62N) form N-H•••O hydrogen bonds with 6-atoms in the hydrogen bond ring (C6 turns). An αβ hybrid C11 hydrogen bonded turn is characterized in the dipeptide Piv-Pro-β3,3Ac6c-NHMe, which is distinctly different from the C11 hydrogen bonds observed in αβ hybrid peptide helices. Several unique structural features such as a dynamic disorder of the hydrogen atom of the carboxylic acid group (in BBAC) and cis geometry of the urethane bond (in BBAC, BAC62N and BPBAC) have been observed in this study. A comparison of the backbone conformations of β3,3Ac6c with other β- amino acid residues is also provided. Chapter 9 describes the crystallographic characterization of a new polymorph of gabapentin monohydrate and crystal structures of the zwitterions of E and Z isomers of tert-butylgabapentin and its hydrochloride and hydrobromide (Vasudev et al., 2009). A comparison of the crystal structures of the monoclinic form (Ibers, J. A. Acta Crystallogr. 2001, C57, 641-643) of gabapentin monohydrate and the newly characterized orthorhombic form reveals identical molecular conformations and intermolecular hydrogen bond patterns in both the polymorphs. The two polymorphs show differences in the orientation of molecules constituting a layer of hydrophobic interactions between the cyclohexyl side chains. A comparison of the packing arrangements of the zwitterionic amino acid molecules in the crystal structures of gabapentin monohydrate, the tert-butyl derivatives and other co-crystals of gabapentin that had been characterized so far, is provided which would facilitate prediction of new polymorphs of the widely used drug molecule, Gpn. Chapter 10 describes the crystallization of α-peptide helices in multiple crystal forms (Vasudev et al., 2008b). Crystal structures of two peptides, Boc-Leu-Aib-Phe-Phe-Leu-Aib-Ala-Ala-Leu-Aib-OMe (LFF), Boc-Leu-Aib-Phe-Ala-Leu-Ala-Leu-Aib-OMe (D1) in two crystal forms and the crystal structure of a related sequence, Boc-Leu-Aib-Phe-Ala-Phe-Aib-Leu-Ala-Leu-Aib-OMe (D10) permit an analysis of the molecular conformation and packing patterns of peptide helices in crystals. The two polymorphs of LFF, crystallized in the space groups P21 and P22121, reveal very similar molecular conformation (α/310-helix) in both the polymorphic crystals; the two forms differ significantly in the pattern of solvation. The crystal structure determination of a monoclinic (P21) and an orthorhombic polymorph (P21212) of D1 provides five different peptide conformations, four of which are α-helical and one is a mixed 310/α-helix. The crystal structure determination of the three peptides provide an opportunity to compare the nature and role of aromatic interactions in stabilizing molecular conformation and packing and its significance in the observation of polymorphism. An analysis of the Cambridge Structural Database and a model for nucleation of crystals in hydrophobic peptide helices are also discussed.