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You are here: Home Science & Projects Deisa Extreme Computing Initiative Projects 2009 - 2010 Understanding the Dynamics of Molecular Machines to Design New Anti-Cancer Molecules.

Understanding the Dynamics of Molecular Machines to Design New Anti-Cancer Molecules.

Research Area Bio Sciences
Principal Investigator(s) Giorgio Colombo
  • National Research Council (CNR), Istituto di Chimica del Riconoscimento Molecolare, Italy
  • Universitat Autònoma de Barcelona, Institute of Biotechnology and Biomedicine, Spain
  • Utrecht University, Bijvoet Center for Biomolecular Research, The Netherlands


Dynamic processes underlie the functions of all proteins. Hence, to understand, control, and design protein functions in the cell, we need to unravel the basic principles of protein dynamics. This is fundamental in studying the mechanisms of a specific class of proteins known as molecular chaperones, which oversee the correct conformational maturation of other proteins. In particular, molecular chaperones of the stress response machinery have become the focus of intense research, because their upregulation is responsible for the ability of tumor cells to cope with unfavorable environments. This is largely centered on the expression and function of the molecular chaperone Hsp90, which has provided an attractive target for therapeutic intervention in cancer. Experiments have shown that the chaperone functions through a nucleotide-directed conformational cycle: as a consequence, understanding the dynamics of this process at the atomic level is a fundamental prerequisite for the development of new pharmacological therapies.
The main goal of this proposal is to develop a highly integrated and robust platform of computational biology, MD simulations and new approaches and tools for (a) probing and elucidating molecular mechanisms of Hsp90 function; and (b) developing broadly applicable, structure-and-dynamics based approaches to design and develop novel Hsp90 inhibitors into clinically relevant Hsp90 targeted drugs for the treatment of various cancers.
Our fundamental goal is to understand molecular mechanisms of ligand-based modulation and inter-domain communications in the molecular chaperone to provide a fundamental basis for the mechanism-based design of new Hsp90 modulators to regulate functional protein motions linked to biological activities. In this application, we propose an integrated system of computational approaches focused on understanding molecular determinants of ligand based modulation and structure-dynamics-function relationships in Hsp90. The use of dynamic information in designing new inhibitors represents an innovative and useful approach to the discovery of new pharmacologically important molecules.

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