Enzymatic Flexibility and Reaction Rate: A QM/MM Study of HIV-1 Protease

• Type: Article in International Scientific Journal
• Date: 2015-08-20

Authors

Pedro A Fernandes (Author) FCUP; António J. M. Ribeiro (Author) Other; Diogo Santos-Martins (Author) Other; Ramos, MJ (Author) FCUP

Journal

Title: Acs Catalysis

Vol. 5

Pages: 5617-5626

ISSN: 2155-5435

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 66 Citations

Scopus - 66 Citations

Other information

Authenticus ID: P-00G-NCT

DOI: 10.1021/acscatal.5b00759

Abstract (EN): The relevance of conformational fluctuations on enzyme rates has been a matter of debate for decades. Single molecule experiments have detected variations on the catalytic rates between different enzyme molecules, and within the same enzyme molecule, in a time scale larger than turnover. Computational methods can detect different energy barriers, induced by thermal conformational fluctuations, at a microscopic time scale, several orders of magnitude faster than the turnover rate of the fastest enzyme. Others have observed these barrier fluctuations, but few computational studies have dissected them in detail and tried to understand their origins and consequences. For this purpose, we studied the first step of the reaction 1 catalyzed by HIV-1 Protease, starting from 40 different conformations. We found activation free energies ranging from 14.5 to 51.3 kcal.mol(-1). The calculated apparent barrier is 16.5 kcal center dot mol(-1), which is very close to the experimental value of 15.9 kcal center dot mol(-1) for product release. These fluctuations are determinant to the overall rate, and these are correlated to specific structural changes. The effect of each enzymatic conformation on the stabilization of the transition state can be explained by the electrostatic interaction of every protein residue with the flow of net electronic density (negative charge) from the reactants to the transition state.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10