Projects that meander randomly into the main stream.

Functional changes in proteins: a computational trek A protein undergoes morphing in its shape as it performs a particular function. Owing to the complexity of the process, for years it has been only the end-points of this journey that have been determined.  This has been possible due various experimental techniques, most notably X-ray crystallography and more recently NMR, electron microscopy etc. The interesting bits in-between have largely remained unknown and have been either hypothesized or indeed largely ignored, owing to the lack of data. However developments in software and hardware now enable the charting of this territory using computer simulations (and more recently, certain exotic experimental techniques).  My research (and that hopefully of my group) is on mapping and understanding these conformational and functional changes in proteins/DNA using theoretical (mostly computational) techniques. A wide range of biologically relevant motions in systems as disparate as nuclear receptors, lipases, IGFs and prions are the focus of research

current collaborators: Stefan Fischer (Univ Heidelberg); Ole Olson (Novo Nordisk, Copenhagen); Ashley Pike (York); G Dodson (NIMR)

Enzyme mechanisms: Recent developments in fast and cheap computation of protein electrostatics using the Poisson-Boltzmann paradigms have revolutionized the field of structural biology by revealing rich and new insights into protein stability/function. Its use in understanding enzyme mechanisms, particularly as a function of multiple and complex ionization profiles are examined in the cysteine proteinase family of enzymes in complement with extensive experimentations The work is complemented with extensive molecular dynamics simulations. Computations are also used to investigate the redox properties of the flavodoxins. Simple models are also being correlated with activity in development of therapeutic proteins

current collaborators: Keith Brocklehurst (Univ London); G Dodson (NIMR)

Flexibility and ligand binding A related area of interest and wider general importance is the coupling of flexibility (motion) and function and how ligand binding modulates this. Using bound water as a paradigm for this, we examine the nature of changes in the motions that accompany ligand binding. In order to examine the thermodynamics of the underlying processes we have been attempting to develop entropic measures that are quick and easy to compute. We are also examining the process of ligand migration in general (an aspect of which is ligand binding)

current collaborators: Stefan Fischer (Univ Heidelberg; Gloria Fuentes (Univ Uterecht, Holland); A. Ballesteros, SCIS, Madrid)

Proteins under extreme conditions It is now being widely recognized that proteins present a rich resource for exploitation in biotechnological applications ranging from bioremediation to construction of computational media such as storage devices. Research is focused on the effects of extreme conditions on the structures and functions of proteins using techniques of molecular dynamics

current collaborators: V. Renugopalakrishnan (FIU, Harvard); J. Whittingham (York)

Motor proteins Several proteins perform their functions by assembling into oligomers and drive processes through the hydrolysis of ATP. One such is the family of proteases in the cell that are responsible for removing misfolded or partly folded proteins.  The common feature of these proteases is an oligomeric structure with a narrow central pore. One such protease is membrane bound FtsH which is responsible for degrading misassembled membrane proteins in bacteria. We have been examining the ATPase domain of this protease through crystallography, extensive mutagenesis and detailed modeling in an attempt to determine the basic principles underlying recognition, unfolding and translocation to the digestion chamber by this assembly

current collaborators: Teru Ogura (Kumamoto, Japan); A.J. Wilkinson, M Brzozowski (York)

Large scale dynamics  The holy grail of current in-silico experiments is to simulate events that may be directly compared with laboratory experiments or that may generate even a hint of  an interest from a  biologist. The former is generally more charitable as it encompasses events that are only a few orders of magnitude larger. Current simulation protocols encompass timescales of the order of nanoseconds while in the laboratory frames, the timescales are milli to muicroseconds at the very least. Of course there are simulation methods that have been engineered to overcome this barrier (called activated dynamics, reaction paths etc etc) on the one hand while ultrafast experimental techniques are probing events that are really explorable by simple simulations as well, these experiments are recent and relatively few in number (and attempts). In an attempt to bridge the temporal (and spatial) gaps, bridges need to be built in the way we analyze data. This requires the development of ideas that have their origins in the field of nonlinear dynamics/non-equilibrium thermodynamics.

current collaborators: Leo Caves (York); John Straub (Boston)

General meanderings  The above mentioned techniques are brought together in varying combinations and have been very useful in establishing models for various biochemical/biophysical/biological and often therapeutic processes. These include studies on the progesterone receptor, estrogen receptor, chaperones, insulins (diabetes), factor VIIA (blood coagulation), drug-resistance in bacteria, drug-resistance in humans.

current collaborators: Norman Maitland (York);  David Roper (Warwick); Shekhar Mande (CDFD, Hyderabad)