Kinetic and Thermodynamic Studies of Molecular Machines and Oscillatory Processes
S. Roy Caplan
Dept. of Biological Chemistry
Weizmann Institute of Science
Tel. (+972)-8-9342454, Fax. (+972)-8-9344112,
Life Sciences Open Day 2002

Objectives of Research:

These studies (which involve collaborations with colleagues in Israel, Switzerland, Canada, and the U.S.A.) are directed toward elucidating the mechanisms and energetics of energy transduction and oscillation in biochemistry and physiology. The techniques used are mathematical modelling and computer simulation based on experimentally determined parameters, taking into account the kinetics and thermodynamics of the system. Recent work includes the bacterial flagellar motor, focusing on both the switching and torque-generating processes, and the genesis of the ultradian rhythm of growth hormone secretion.

Recent Findings:

Switching flagellar rotation from one direction to another is an essential part of bacterial chemotaxis. We have demonstrated that fumarate facilitates the switching of the flagellar motor from counter-clockwise rotation to clockwise rotation by reducing the standard free energy difference of the switching transition. In attempting to understand the rotary mechanism, we have developed an electrostatic model for the flagellar motor which, in contrast to similar approaches developed earlier, reproduces closely a large number of experimental findings including the nonlinear behavior of the torque-frequency relation in E. coli, the stoichiometry of the system, and the stepping character of the motor. It demonstrates that the proton flux through the motor and the rotation are tightly coupled.

Growth hormone (GH) induces growth in animals and humans and also has important metabolic functions. The typical GH profile in the male rat shows secretory episodes every 3.3 h. Focusing on the mechanisms generating this rhythm we simulated the time course of GH secretion under a variety of conditions. The model we propose is based on feedback of GH on its own release mediated both by GH receptors on somatostatin (SRIF) neurons in the brain and by a delayed SRIF release into both the brain and portal blood. This affects both the somatotroph cells in the pituitary and the GH-releasing hormone (GHRH) neurons in the hypothalamus. The secretion of GHRH is postulated to occur in an approximately 1-h rhythm modulated by the level of SRIF. The model predicts a possible mechanism for the feminization of the male GH rhythm by sex steroids and vice versa, and suggests experiments that might reveal the proposed intrinsic 1-h GHRH rhythm.

Recent Publications:

Walz, D. and Caplan, S.R. Nonequilibrium thermodynamics and kinetics. (1995) In: Caplan, S.R., Miller,I.R., and Milazzo, G. (eds.) "Bioelectrochemistry: Principles and Practice, Vol. 1. Bioelectrochemistry: General Introduction", Birkhäuser Verlag, Basel, pp. 1-48.

Walz, D., Caplan, S.R., Scriven, D.R.L., and Mikulecky, D.C. Methods of mathematical modelling. (1995) In: Caplan, S.R., Miller,I.R., and Milazzo, G. (eds.) "Bioelectrochemistry: Principles and Practice, Vol. 1. Bioelectrochemistry: General Introduction", Birkhäuser Verlag, Basel, pp. 49-131.

Raif-Preminger, M., Caplan, S.R., and Yuli, I. (1995) Temporal segregation in signalling: a novel mechanism in human neutrophils. Biochim. Biophys. Acta 1265: 49-54.

Welch, M., Margolin, Y., Caplan, S.R., and Eisenbach, M. (1995) Rotational asymmetry of Escherichia coli flagellar motor in the presence of arsenate. Biochim. Biophys. Acta 1268: 81-87.

Kara-Ivanov, M., Eisenbach, M., and Caplan, S.R. (1995) Fluctuations in rotation rate of the flagellar motor of Escherichia coli. Biophys. J. 69: 250-263.

Walz, D. and Caplan, S.R. (1995) Chemical oscillations arise solely from kinetic nonlinearity and hence can occur near equilibrium. Biophys. J. 69: 1698-1707.

Turner, L., Caplan, S.R., and Berg, H.C. (1996) Temperature-induced switching of the bacterial flagellar motor. Biophys. J. 71: 2227-2233.

Prasad, K., Caplan, S.R., and Eisenbach, M. (1998) Fumarate modulates bacterial flagellar rotation by lowering the free energy difference between the clockwise and counterclockwise states of the motor. J. Mol. Biol. 280: 821-828.

Wagner, C., Caplan, S.R., and Tannenbaum, G.S. (1998) Genesis of the ultradian rhythm of GH secretion: a new model unifying experimental observations in rats. Am. J. Physiol. 275 (Endocrinol. Metab. 38): E1046-E1054.

Walz, D. and Caplan, S.R. (1998) An electrostatic model of the bacterial flagellar motor. Bioelectrochem. and Bioenergetics, 47: 19-24.

Eisenbach, M. and Caplan, S.R. (1998) Bacterial chemotaxis: Unsolved mystery of the flagellar switch. Current Biology 8: R444-R446.

Caplan, S.R. and Walz, D. (1999) The bacterial flagellar motor: a brief review of models, and a new electrostatic model. In: Bersani, F. (ed.) "Electricity and Magnetism in Biology and Medicine", Plenum, N.Y., pp. 251-254.

Walz, D. and Caplan, S.R. An electrostatic mechanism closely reproducing observed behavior in the bacterial flagellar motor. Biophys. J. 78, 626-651 (2000).

Caplan, S.R. and Johnstone, R.M. (2001). Non-equilibrium thermodynamics and kinetics of the multidrug transporter. In: Raffa, R.B. (ed.) "Drug-Receptor Thermodynamics: Introduction and Applications", Wiley, N.Y., pp. 701-740.

Walz, D. and Caplan, S.R. (2002). Bacterial flagellar motor and H+/ATP synthase: two proton-driven rotary molecular devices with different functions. Bioelectrochemistry 55, 89-92.

Walz, D. and Caplan, S.R. (2005). A Kinetic and Stochastic Analysis of Crossbridge-Type Stepping Mechanisms in Rotary Molecular Motors. Biophys. J. 89, 1650-1656.

Gakamsky, A., Schechtman, E., Caplan, S.R., and Eisenbach,M. (2008) Analysis of chemotaxis when the fraction of responsive cells is small - application to mammalian sperm guidance. Int. J. Dev. Biol. 52, 481-487.

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