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Published December 19, 2000 | Published
Journal Article Open

Femtosecond studies of protein-ligand hydrophobic binding and dynamics: Human serum albumin


In this contribution, we report studies of the nature of the dynamics and hydrophobic binding in protein-ligand complexes of human serum albumin with 2-(2'-hydroxyphenyl)-4-methyloxazole. With femtosecond time resolution, we examined the orientational motion of the ligand, its intrinsic nuclear motions, and the lifetime changes in the hydrophobic phase. For comparisons, with similar but chemical nanocavities, we also studied the same ligand in micelles and cyclodextrins. The hydrophobic interactions in the binding crevice are much stronger than those observed in cyclodextrins and micelles. The confined geometry restrains the nonradiative decay and significantly lengthens the excited-state lifetime. The observed dynamics over the femtosecond-to-nanosecond time scale indicate that the binding structure is rigid and the local motions of the ligand are nearly "frozen" in the protein. Another major finding is the elucidation of the directed dynamics by the protein. Proton transfer and intramolecular twisting of 2-(2'-hydroxyphenyl)-4-methyloxazole were observed to evolve along two routes: one involves the direct stretching motion in the molecular plane (approx 200 fs) and is not sensitive to the environment; the second, less dominant, is related to the twisting motion (approx 3 ps) of the two heterocyclic rings and drastically slows down in the protein hydrophobic pocket.

Additional Information

© 2000, The National Academy of Sciences. Contributed by Ahmed H. Zewail, October 16, 2000. We thank Ms. Irene García-Ochoa, Dr. Spencer Baskin, and Dr. Chaozhi Wan for their help. This work was supported by the National Science Foundation. All experiments were performed at the Laboratory for Molecular Sciences at Caltech. A.D. was supported by the U.S.–Spain cooperative program and by the Ministry of Education and Science (Spain). The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.250491297. Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.250491297

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