Research Description
Folding of newly synthesized peptide(s) into an active, native form of a protein encompasses broad ranges of structural dynamics. The model is proposed to explain the folding of staphylococcal nuclease (SNase) by T.Y. Tsong and colleagues (to be published). The protein in its active form assumes the conformation shown in the lower rightmost structure (cis-P117). The Structure is composed of two discernible domains, the N-domain and the C-domain. Folding starts from presumably an ensemble of conformations with no intramolecular interaction energy. These reactions, taking place between ns and us, represent events of small activation processes. They give rise to less than 10% of the circular dichroism signal. They are not represented in this figure. The events that follow are the formation of the hydrophobic clusters, semi-independently, in the N-domain and the C-domain. These events take place in 10-50 ms. The accumulation of helices and sheets inside the newly formed hydrophobic clusters is slow, in 50 ms to 2 s, presumably because of the crowded environment. The interlocking of the N-domain and C-domain then takes place in 6 s. the formation of two active forms (trans-P117 and cis-P117) requires further structural fine-tuning and it takes place in 35 s. The trans to cis isomerization of proline 117 is slow. However, both forms of the enzyme exhibit full nuclease activity. The stability of the enzyme in cis-P117 and trans-P117 is similar, approximately 8 kbT. Almost the entire 8 kBT of the conformational stability of the native state is acquired at the last step in folding. However, these kinetic steps have activation barriers ranging from 25 kBT to 30 kBT. Experiments show that the Least Activation Path (LAP) dictates the pathway of protein folding. In other words, the population trots the deepest valleys of the activation energy landscape to arrive at the global free energy minimum of the native state. Multiple pathways will result if the activation barriers of different pathways have similar heights.
Tsong, TY, Chang, CH. Catalytic wheel, Brownian motor, and biological energy transduction. AAPPS-Bull. 13-2:12-18 (2002). (pdf-file-01)
Theory of catalytic wheel, Brownian motor and Markovian engine
Michaelis-Menten Enzyme (MME) as catalytic wheel
The two chemical equations represent the complete catalytic process of the Mechaelis-Menten Enzyme mechanism. The enzyme binds a substrate and the substrate is converted to product and released and the enzyme recycles. The enzyme turns over in each catalytic cycle, and is best treated as a catalytic wheel.
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Brownian motor and Brownian ratchet
The MME enzyme will behave like a Brownian motor. Electric field-enforced conformational oscillation induces pumping of a ligand from the left compartment to right when the activation barrier of the ligand and proteins are as shown. An enzyme or molecular pump is constructed to pump a ligand leftward or rightward by the design of the chemical activation barrier of the two compartments.
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Current Curriculum Vitae (2008)
Address: 7 Dove Lane, North Oaks, MN, 55127
Professional Experience:
Natl Chiao-Tung Univ, Taiwan Chair Professor (2005-2008)
NDL, Hsinchu, Taiwan Distinguished Chair (2005-2007)
Inst of Phys, Acad Sci Distinguished Professor (2003-2008)
Natl Chung-Hsing University Chair Professor (2003-2005)
Dept Phys, Natl Taiwan Univ University Chair (2001 and 2002)
Dept Bioch, Univ of Minnesota Professor of Biochemistry (1988-2004)
Dept Bioch, Hong Kong Univ Sci & Technol Professor of Biochem (1992-1997)
Biotech Research Inst, Hong Kong Univ Sci & Technol Director (1993-1996)
Dept Biol Chem, Johns Hopkins University School of Medicine Asst & Assoc Prof (1972-1987)
Dept Bioch, Stanford Univ Post Doctoral Fellow (1970-1971)
Education:
Dept Chem, National Chung-Hsing University BS (1960-1964)
Dept Chem, Yale University MS (1965-1967)
Dept Chem, Yale University PhD (1967-1969)
Other Professional Activities:
Fritz-Habar Inst, Berlin Invited Guest Scientist (1986 summer)
Inst Mol Sci, Oxford University Invited Guest Scientist (1996 summer)
Inst Mol Biol, Swiss Fed Inst (ETH) Invited Academic Guest (1996 fall)
Natl Inst Standard Technol Adjunct Professor (1987-1988)
A NIH Study Section Member (1976-1980)
Biophys J Associate Editor (1990-1991)
Biophys J Editorial Board (1990-1997)
J Biomembr Bioenerg Editorial Board (1990-2007)
Inst of Phys, Acad Sci. Advisory Comm (2001-2007)
Ctr Nanosci Nanotech, Taiwan Univ Sys, Steering Comm (2003-2005)
Ctr Nanosci Nanotech, Natl Chung-Hsing Univ, Adv Comm (2002-2008)
Col of Sci, Natl Chiao-Tung Univ Advisory Comm (2006-2008)
Genomic Research Center, AS Science Advisory Board (2006-2008)
Representative Publications in Different Areas
Softmatter Characteristics of Proteins and Mechanisms of Protein Folding
5. Tsong, T.Y., Sturtevant, J.M. et al. (1970). A Calorimetric Study of the Thermally-Induced Conformational Transitions of Ribonuclease-A and Certain of Its Derivatives. Biochemistry 9, 2666-2677.
7. Tsong, T.Y., Baldwin, R.L., Elson, E.L. (1971). The Sequential Unfolding of Ribonuclease A: Detection of Fast Initial Phase in Kinetics of Unfolding. Proc. Natl. Acad. Sci. 68, 2712-2715.
8. Tsong, T.Y., Baldwin, R.L., McPhie, P. (1972). A Sequential Model of Nucleation-Dependent Protein Folding. J. Mol. Biol. 63, 453-475.
22. Tsong, T.Y. (1976). Ferricytochrome c Chain Folding Measured by the Energy Transfer of Trp-59 to the Heme Group. Biochemistry 15, 5467-5473.
29. Kanehisa, M.I., Tsong, T.Y. (1978). Cluster Model of Lipid Phase Transitions with Application to Passive Permeation of Molecules and Structure Relaxations in Lipid Bilayers. J. Am. Chem. Soc. 100, 424-432.
32. Kanehisa, M.I., Tsong, T.Y. (1978). Mechanism of Multiphasic Kinetics in the Unfolding and Refolding of Proteins. J. Mol. Biol. 124, 177-194.
37. Tsong, T.Y., Karr, T., Harrington, W. (1979). Rapid Helix-Coil Transition in the S-2 Region of Myosin. Proc. Ntal. Acad. Sci. 76, 1109-1113.
59. Harrington, W., Ueno, H., Tsong, T.Y. (1983). Cross-Bridge Movement in Muscle and the Conformation of the Myosin Hinge. Ciba Foundation Symposium. 93, 186-207.
106. Bertazzon, A., Tsong, T.Y. (1990). Study of Effects. Of pH on the Stability of Domains in Myosin Rod by High Resolution Differential Scanning Calorimetry. Biochemistry 29, 6453-6459.
135. Chen, H.M., Markin, V.S., Tsong, T.Y. (1992). Kinetic Evidences of Microscopic States in Protein Folding. Biochemistry 31, 12369-12375.
166. Su, Z.D., Tsong, T.Y. et al. (1996). Least Activation Path for Protein Folding. Proc. Natl. Acad. Sci. 92, 2539-2544.
Electroporation and Electrofusion of Cell Membranes and Its Applications
23. Kinosita, K., Tsong, T.Y. (1977). Hemolysis of Human Erythrocytes by a Transient Electric Field. Proc. Natl. Acad. Sci. 74, 1923-1927.
26. Kinosita, K., Tsong, T.Y. (1977). Formation and Resealing of Pores of Controlled Sizes in Human Erythrocyte Membranes. Nature 268, 438-441.
31. Kinosita, K., Tsong, T.Y. (1978). Survival of Sucrose-Loaded Erythrocytes in Circulation. Nature 272, 258-260.
51. Teissie, J., Tsong, T.Y. et al. (1982). Electric Pulse-Induced Fusion of 3T3 Cells in Monolayer Culture. Science 216, 537-538.
65. Lo, M.M.S., Tsong, T.Y. et al. (1984). Surface Antibody Mediated, Electric Field Induced Cell Fusion: Specific and Efficient Production of Monoclonal Antibodies. Nature 310, 792-794.
127. Tsong, T.Y. (1991). Electroporation of Cell Membranes. Biophys. J. 60, 297-306.
Electric Field Induced Cation Pumping by Na,K-ATPase and Theory of Brownian Ratchets and Brownian Motors
41. Teissie, J., Tsong, T.Y. (1980). Evidence of Voltage Induced Channel Opening in Na,K-ATPase of Human Erythrocyte Membranes. J. Membrane Biol. 55, 133-140.
55. Serpersu, E.H., Tsong, T.Y. (1983). Stimulation of Rb-Pumping Activity of Na,K-ATPase in Human Erythrocytes with an External Electric Field. J. Membrane Biol. 74, 191-201.
70. Tsong, T.Y., Astumian, R.D. (1986). Absorption and Conversion of Electric Field Energy by Membrane Bound ATPase. Bioelectrochem. Bioenerg. 15, 457-476.
71. Westerhoff, H., Tsong, T.Y. et al. (1986). How Enzyme Can Capture and Transmit Free Energy from an Oscillating Electric Field. Proc. Natl. Acad. Sci. 83, 4734-4738.
77. Tsong, T.Y. (1987). Electroconformational Coupling and Membrane Protein Function. Prog. Biophys. Mole. Biol. 50, 1-45.
116. Tsong, T.Y. (1990). Electri Modulation of Membrane Proteins. Annu. Rev. Biophys. Biophys. Chem. 19, 83-106.
167. Xie, T.D., Tsong, T.Y. et al. (1997). Noise-Induced Flux in Biochemical Cycle. Biophys. J. 72, 2496-2502.
Publications of the Past Several Years
176. Tsong, T.Y. (2002). Electroconformational Coupling for Biological Energy and Signal Transduction. In "Bioelectrochemistry of Membrane", Eds., Teissie, J. and Walz, D., Birkhauser Publishing, Switzerland. Pp. 151-172.
177. Tsong, T.Y. and Xie, T.D. (2002). Ion Pump as Molecular Ratchet and Effects of Noise: Electric Activation of Action Pumping by Na,K-ATPase. Apply. Phys. A-Mater 75(2), 345-352.
178. Tsong, T.Y. (2002). Na,K-ATPase as A Brownian Motor: Electric Field-induced Conformational Fluctuation Leads to Uphill Pumping of Cation in the Absence of ATP. J. Biol. Phys. 28 (2), 309-325.
186. Chang, C. H. and Tsong, T. Y. (2003). Truncation and Reset Process on Parrondo's Paradox and Flashing Ratchet. Proc. Intl. Conf. Noise And Fluctuations.
187. Chang, C. H. and Tsong T. Y. (2003). Truncation and Reset Process on the Dynamics of Parrondo's Games, Phys. Rev. E 67 (2), art. No. 025101.
188. Tsong, T. Y. and Chang, C. H. (2003). Ion Pump as Brownian Motor: Theory of Electroconformational Coupling and Proof of Ratchet Mechanism for Na,K-ATPase Action, Physica A 321 (1-2), 124-138.
189. Tsong, T. Y. and Chang, C. H. (2003). Catalytic Wheel, Brownian Motor, and Biological Energy Transduction, AAPPS Bulletin, Vol. 13, No. 2, Pp. 12-18.
190. Makhnovskii, Y. A., Rozenbaum, V. M., Yang, D. Y., Lin, S. H., and Tsong, T. Y. (2004). Flashing Ratchet Model with High Efficiency, submitted to Phys. Rev. E. 69, 021102.
191. Chang, C. H. and Tsong, T. Y. (2004). Stochastic Resonance in an Ion Pump under Complex Fluctuations. Phys. Rev. E. 69, 021914.
192. Rozenbaum, V. M., Yang. D. A., Lin, S. H. and Tsong, T. Y. (2004). Catalytic Wheel as a Brownian Motor. J. Phys. Chem. B 108, 15880-15889.
193. Su, Z. D., Wu, J. M., Tsong, T. Y. and Chen, H. M. (2004). Modular Assembly Revealed by Tryptophan and Other Optical Probes in Staphylococcal Nuclease Folding. J. Chin. Chem. Soc. Taipei 51, 1099-1106. Special Issue commemorating the 67 th Birthday and his retirement from professional life of Sunney I. Chan.
194. Chang, C. H. and Tsong, T. Y. (2004). Symmetry Breaking Induced Directed Motions. Proceeding of the Sicily Symposium on Nonlinear Dynamics. 5 pages.
195. Tsong, T. Y. and Chang, C. H. (2005). Enzyme as Catalytic Wheel Powered by a Markovian Engine: Conformational Coupling and Barrier Surfing Models. Physica A. 350, 108-121.
196. Chang, C. H. and Tsong, T. Y. (2005). Stochastic Resonance of Na,K-ion Pumps on the Red Cell Membrane. Proceeding of Symposium in Spain (4 pages).
197. Rozenbaum, V. M., Korochkova, T. Ye., Yang, D.-Y., Lin, S. H. and Tsong, T. Y. (2005). Two Approaches toward a High Efficiency Flashing Ratchet. Phys. Review E 71, 041102.
198. Tsong, T. Y. and Chang, C. H. (2005). Catalytic Wheel, Brownian Motor, and Biological Energy Transduction. J. Chin. Phys. Soc., Taipei. 43, 273-284.
199. Su, Z.D., Wu, J.M., Fang, H.J., Tsong, T.Y. and Chen, H.M. (2005). Local Stability Identification and the Role of Key Aromatic Amino Acid Residue in the Staphylococcal Nuclease Refolding. FEBS. J. 272, 3960-3966.
200. Chen, H.M., Chan, S.C., Leung, K.W., Wu, J.M., Fang, H.J. and Tsong, T.Y. (2005). Local Stability Identification and the Role of Key Acidic Amino Acid Residues in Staphylococcal Nuclease Unfolding. FEBS J. 272, 3967-3974.
201. Chang, C. H. and Tsong, T. Y. (2005). Dipole Ratchet for Rotary Molecular Motor. Phys. Rev. E 72, 051901.
202. Rozenbaum, V. M., Yang, D.-Y., Lin, S. H. and Tsong, T. Y. (2006). Energy Losses in A Flashing Ratchet with Different Potential Well Shape. Physica A. 363, 211-216.
203. Makhnovskii, Y. A., Rozenbaum, V. M., Yang, D.-Y., Lin, S. H. and Tsong, T. Y. (2006). Reciprocating Nanoengine. Eur. Phys. J. B. 52, 501-505.
204. Tomita, M., Fukuda, T., Ozu, A., Kimura, K. I., Tsong, T. Y. And Yoshimura, T. (2006). Antigen-Based Immunofluorescence Analysis of B-Cell Targeting: Advanced Technology for the Generation of Novel Monoclonal Antibodies with High Efficiency and Selectivity. Hybridoma. 25, 283-292.
205. Tsong, T. Y. and Chang, C. H. (2007). A Markovian Engine for Biological Energy Transducer: The Catalytic Wheel. BioSystems. 88, 323-333.
206. Chang, C. H. and Tsong, T. Y. (2007). Energy Transduction in Molecular Machines. NANO 2, 273-280.
207. Chow, C.-Y. Wu, M.-C., Fang, H.-J., Hu, C.-K., Chen, H.-M. and Tsong, T. Y. (2008). Compact Dimension of Denatured States of Staphylococcal Nuclease. Proteins: Struct. Func. Bioinfor. In press.
208. Tsong, T. Y., Hu, C.-K., and Wu, M.-C. (2008). Hydrophobic Condensation and Modular Assembly Model for Protein Folding. BioSystems. In press.
209. Chang, C.-H. and Tsong, T. Y. (2008). Stochastic Resonance of Na, K-ion Pumps on Cell Membranes. Proceeding of the Fifth Intl. Conf. on Unsolved Problems on Noise. In press.
210. Fang, H.-L., Chen, Y.-L., Li, M.-S., Chen, Y.-Z., Wu, M.-C., Chang, C.-L., Chang, C.-K., Hsu, Y.-L., Huang, T.-H., Chen, H.-M., Tsong, T. Y., and Hu, C.-K. (XXXX). Differential Scanning Calorimetry, Circular Dichroism, and Go-like Model Approach to the Folding of the N-terminal RNA-binding Domain of the SARS-CoV Nucleocapsid Protein, Submitted.
211.Hu, H.-Y., Wu, M.-C., Fang, H.-J., Forrest, M.-D., Hu, C.-K., Tsong, T. Y. and Chen, H.-M. (XXXX). Role of Tryptophan in Staphylococcal Nuclease Stability. In preparation.
212. Jiang, S.-L., Chen, Y.-Z., Fang, H.-J., Wu, M.-C., Chang, C.-L., Hu, C.-K., Chen, H.M. and Tsong, T. Y. (XXXX). Effects of Ions and pH on the Thermal Stability of Hen Egg-white Lysozyme. In preparation.
Symposia and Conferences
Invited keynote and plenary lecturer to more than 150 national (USA) and international symposia and conferences, including several Gordon Research Conferences, Chien Su-Liang Memorial Lecture, and an invited participant to the Nobel Symposium 131.
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