V. Carnevale, S. Raugei, C. Micheletti and P. Carloni
Large-scale motions and electrostatic properties of Furin and HIV-1 protease
J. Phys. Chem A 111 12327-12332 (2007)
Link to online article.
ABSTRACT
We present a comparative study between two members of serine and
aspartic proteases complexed with a peptide substrate. The same
computational setup is used to characterize the structural,
electrostatic, and electronic properties for the Michaelis complex of
furin, a serine protease, and of the aspartic protease from HIV-1. In
both cases plane-wave density functional theory (PW-DFT) and empirical
force-field-based molecular dynamics calculations are used. For furin,
calculations are extended to the complex with the intermediate of the
first step of the reaction. Comparisons are also made with results
from recent PW-DFT investigations on both families of enzymes and with
the same chemical groups in an aqueous environment. It is found that
the substrate carbonyl group is more polarized in the furin complex
than in the HIV-1 protease one. A further difference regards the
large-scale motions of the complexes as a whole and local
conformational fluctuations at the active site. The global and local
fluctuations are well coupled for HIV-1 protease but not for furin.
Thus, despite some chemical analogies in the first step of the
reaction mechanism, furin and HIV-1 protease complexes appear to be
characterized by a different interplay of electrostatics and
conformational fluctuations.