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An exploration of the cprrelations between melting point and molecular and crystal structures has been made. The research was based on a training set with 100 compounds in which the molecular structures contain one common, core unit with two various terminal groups. Previous work by Dr Gelbrich of our group confirmed that the crystal structures of the training set comprise 56 different structure types containing nine different types of hydrogen bonding arrangements. The investigation was divided in three main parts which focused on (1) the effect of molecular structures pn melting point, (2) the influence of different crystal structures on melting point and (3) a statistical approach to the correlation of melting point with chemical descriptors derived from molecular and crystal structures. Part one focused on exploring how the two terminal groups affect a compound's melting point. The result showed that N02, CN and, I groups at both R1 and R2 positions cause a high meting point whilst Mea, Hand F are related to the low melting point samples. In part two, the crystal structures ofcompounds with two dominant types ofH-bond were explored. The detailed analysis involved attempting to identify and assess all potential intermolecular interactions. Moreover a two-dimensional fingerprint plot generated from Hirshfeld surface has been used to give a better understanding on intermolecular interactions within a crystal structure. In part 3, three melting point prediction equations based on molecular descriptors (R2=41.70%, S=28.5056), crystal structure descriptors (R2=37.00%, S=29.1297) and combined descriptors (R2=54.10%, S=25.4277) respectively.

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The Rho family of smallpTP-binding proteins includes Rndl, Rnd2 and Rnd3/RhoE, which are characterised by their inability to bind to GDP and therefore exist primarily in a GTPbound form. RhoA stimulates stress fibre formation whereas Rndl and Rnd3/RhoE induce the disassembly of actin stress fibres. Both RhoA and RhoE interact with the serine/threonine kinase ROCK I, which is a downstream target for RhoA. This thesis examines the interaction between RhoE and ROCK I and its effect on the actin cytoskeleton. Co-expression ofRhoE with ROCK I in Swiss 3T3 fibroblasts inhibited ROCK I-induced stellate stress fibre assembly. A series of ROCK I deletion mutants were used to identify residues 1-420 ofROCK I as the minimum region required to bind to RhoE. ROCK I 1-420 was successfully purified as an active kinase from mammalian and insect cells, but was insoluble in E. coli. Cross-linking experiments as well as co-expression of GST-mycROCK I 1-420 and myc-ROCK I 1-420 in Cos 7 cells revealed that ROCK I 1-420 forms a dimer. Deletion of the N-terminal region (residues 1-76) of ROCK I prevented dimerisation and RhoE binding suggesting that N-terminus- mediated dimerisation of ROCK I was required for RhoE binding. In addition, ROCK I 375-727, which includes the central coiledcoil domain could form dimers, but was unable to bind to RhoE demonstrating that two regions ofROCK I mediate dimerisation. To identify ROCK I 1-420 autophosphorylation sites, recombinant ROCK I 1-420 produced in baculovirus-infected insect cells was subjected to mass spectrometry analysis and Edman degradation. Eight autophosphorylation sites were identified and the SerlThr sites were mutated to alanine. Of these, Thr-398 phosphorylation was required for ROCK I to form dimers, bind to and phosphorylate RhoE and induce stellate structures in Swiss 3T3 fibroblasts. The findings reported here show that the interaction between RhoE and ROCK I is important for actin cytoskeleton regulation and remodelling.

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