Fellow

Malcolm Irving is Director of the Randall Division of Cell and Molecular Biophysics, King's College London His pioneering methods for characterising molecular motions in cells have broad implications for understanding the relationships between protein structure and function in the cellular environment. Irving’s work has exploited the structural order and functional specialisation of single skeletal muscle cells as a model system for developing new techniques to study protein structure and dynamics in situ. Before this work, fundamental gaps remained in our understanding of the molecular mechanism of muscle contraction. Irving and collaborators developed three novel biophysical techniques based on birefringence, polarised fluorescence and X-ray diffraction that progressively revealed the molecular details of the motions of the myosin heads that drive muscle contraction. Thus they showed that the light-chain binding domains of the heads in intact muscle cells tilt while their catalytic domains are transiently bound to actin. Exploiting the sub-millisecond time resolution of the techniques, they were able to isolate head motions associated with their elasticity, with the ‘working stroke’ that generates force, and with the slower cycling between actin monomers that controls the steady-state mechanical and energetic properties of skeletal muscle. These are the fundamental mechanisms of muscle contraction. Irving has also elucidated some of the molecular structural changes that trigger the activation of skeletal muscle fibres following the transient rise in intracellular calcium concentration by applying the polarised fluorescence technique to components of the troponin complex. He is currently extending this approach to investigate the mechanism of regulation of contractility in the myocardium.