Biography

Dr Brendan J.Howlin joined the University of Surrey in September 1987 to teach on the new computer aided chemistry degree course. He currently teaches visual basic, molecular modelling and inorganic chemistry.

He graduated with BSc and PhD from the University of Essex, having studied the inorganic chemistry of microbial iron transport compounds, using Mossbauer spectroscopy and X-ray crystallography. He also carried out postdoctoral pharmaceutical and protein modelling studies at Birkbeck College in the University of London and Pfizer Ltd.

Brendan Howlin can be contacted on
+44(0) 1483 68 6248 or at
B.Howlin@surrey.ac.uk

Research Interests

Protein modelling

Docking of a flexible ligand to a rigid protein, followed by molecular dynamics (MD) studies to allow movement of the protein is shown to be a useful method for investigating pharmacologically relevant interactions.

Studies of MMB lectins (β -sheet proteins with shallow binding sites) reveal the importance of dimerisation to the activation of all of the carbohydrate binding sites of these lectins, finalising site III into a shape that can accommodate mannose. Aloe lectin was shown to have the overall fold of a MMB lectin and to be capable of forming a dimeric unit, shown to be stable using MD simulations in a water box. Docking shows that only two binding sites in the aloe dimer are thought to be able to bind mannose, as alterations in the residues vital for binding have occurred, and this is supported by the absence of a cluster of docked conformations in these sites.

G-Protein Coupled Receptors. 60% of all pharmaceutical drugs act at g-protein coupled receptors (GPCR's), thus studying how they work is very important for furthering our understanding of how many of our existing therapies work and developing new or improved ones. Docking of atropine to the GPCR m1AchR (an a-helical transmembrane protein with and enclosed binding site) indicates the presence of two key hydrogen bonds with Ser109 and Asn110.

The main influences on docking seem to be shape and size of the ligand rather than charge considerations, although the negatively charged end of the binding pocket orients the molecules in the majority of the dockings in the same direction. Docking studies of atropine and selected analogues to m1AchR and two mutants, Tyr381Phe and Tyr381Ala, produce data which correlate well with experimentally determined pIC50 values and a prediction of pIC50 of previously untested antagonists for this system. Molecular dynamics studies show differential movement in the transmembrane helices for MD studies with acetylcholine, atropine and no ligand bound and rearrangement of some key hydrogen bonds. This leads to a model of inverse agonist functionality for atropine and its analogues involving the prevention of helical movement by the aromatic tail groups of these ligands.

Metabolomics

Researching into Predictive drug metabolism theories. Many oral drugs are metabolised by cytochromes from the P450 family in the liver. The drugs may undergo either or both a phase one reaction and a phase two reaction. Currently working on a predictive program using structural and chemical data of known drugs metabolised by cyrochrome P450 for the prediction of likely metabolites of new lead compounds.

This project is being carried out in collaboration with IDBS

DNA Modelling

Mesocale Modelling of DNA. The understanding of the structural constraints operating at the mesoscale level in DNA is being studied by computer modelling of DNA helices using the technique of Monte Carlo Annealing. Software has been written in house for this application. The potential for DNA to bend depending on the nucleotide sequence of the DNA under study is an area of current interest.

This work is carried out by Dr Kostas Syfrakis in collaboration with Dr. Astero Provata of the NRCPS, "Demokritos", Greece.

Polymer Modelling

Molecular Modelling of Synthetic Polymers. To gain insight into how the chemical structure of the polymer affects its physical and mechanical properties, we have been using molecular modelling to build models of the polymers we are studying and have calculated experimentally measurable parameters e.g. the Young's Modulus of Elasticity, which we have then determined experimentally. The comparison between the calculated and experimental values allows validation of the molecular models. Systems studied include crystalline polyethylene, polyethersulphones and linear epoxy resins, prediction of the physical and mechanical properties of network forming cyanate ester resins, the interaction of resins with carbon fibre surfaces and evaluation of the accuracy of the prediction of polymer structures with specific infra-red characteristics. Recently our interests have expanded to include conducting polymers, e.g. polyparaphenylene and polypyrrole and nanocomposites based on imogolite tubules.

Benzoxazines are a class of synthetic polymers, currently of great interest to the electronics and medical sectors. We are seeking to understand the toughness of these polymers at the atomistic level by molecular simulation. The number of atoms in the unit cell of the polymer chosen for the simulation is critical for these calculations because a larger cell gives more degrees of freedom for the simulation to react to stress, pressure, etc. and thereby models the experimental situation more closely

Computer Simulation of the Kinetics of Polymer Cure or Degradation. The reactions that characterise epoxy resin cure are still relatively poorly understood. The aim of this research is to derive rate constants for the cure of epoxy resins and use this information to design epoxy resin systems that will cure to user defined timescales and conditions.

We concentrated initially on model systems as the intractable systems formed on cure are difficult to analyse chemically; hence we have studied aromatic monofunctional amines and PGE. The combination of radiolabelling and radio-hplc to derive quantitative concentrations of each species with respect to time has allowed us to develop software which solves the rate equations using the fourth order Runge-Kutta approximation and gives as output the rate constants for the reactions. This work has been extended to sytems where linear polymers are formed and we have followed the reaction up to the limit of radio-hplc and into the radio-GPC regime, solving equations involving all species up to and including the oligomer formed between four amines and four BADGE moieties. Recently we have extended this work to include in-line monitoring by NIR and predicting the lifetimes of carbohydrates of industrial interest e.g. insulation in electrical transformers.

Research Collaborations

Collaborate with Dr. Ian Hamerton on Polymer synthesis, characterisation and modelling

Collaborate with Professor Jian_Mei Li on NADPH Oxidases

Publications

Teaching

Teaching Duties include Inorganic Chemistry, spectroscopy and Computer Aided Chemistry. Computer Aided Chemistry teaching includes Visual Basic, Molecular modelling, cheminformatics and DNA profiling for the final year Forensics

Departmental Duties

Director of Postgraduate Research

Affiliations

CCHEM FRSC

Member of the British Crystallographic Association

Member of the Molecular Graphics Society