期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 20, 页码 7636-7641出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1120646109
关键词
solvation thermodynamics; dehydration; protein interface
资金
- National Research Foundation of Korea (NRF)
- Ministry of Education, Science and Technology [KRF-2008-313-C00404, 20090065791, 2011-0012096]
- Korea Institute of Science and Technology supercomputing center
- National Research Foundation of Korea [2010-0023893, 2012R1A2A2A01004687, 2011-0012096, 313-2008-2-C00404] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Hydrophobicity is thought to underlie self-assembly in biological systems. However, the protein surface comprises hydrophobic and hydrophilic patches, and understanding the impact of such a chemical heterogeneity on protein self-assembly in water is of fundamental interest. Here, we report structural and thermodynamic investigations on the dimer formation of full-length amyloid-beta proteins in water associated with Alzheimer's disease. Spontaneous dimerization process-from the individual diffusive regime at large separations, through the approach stage in which two proteins come close to each other, to the structural adjustment stage toward compact dimer formation-was captured in full atomic detail via unguided, explicit-water molecular dynamics simulations. The integral-equation theory of liquids was then applied to simulated protein structures to analyze hydration thermodynamic properties and the water-mediated interaction between proteins. We demonstrate that hydrophilic residues play a key role in initiating the dimerization process. A long-range hydration force of enthalpic origin acting on the hydrophilic residues provides the major thermodynamic force that drives two proteins to approach from a large separation to a contact distance. After two proteins make atomic contacts, the nature of the water-mediated interaction switches from a long-range enthalpic attraction to a short-range entropic one. The latter acts both on the hydrophobic and hydrophilic residues. Along with the direct protein-protein interactions that lead to the formation of intermonomer hydrogen bonds and van der Waals contacts, the water-mediated attraction of entropic origin brings about structural adjustment of constituent monomer proteins toward the formation of a compact dimer structure.
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