Understanding the Dynamics--Activity Relationship in Metalloproteases: Ideas for New Inhibition Strategies

It is known that the dynamic fluctuations in protein structures are essential for their biological functions, including channel gating, allosteric interactions, signal transduction, recognition dynamics and enzymatic catalysis. Understanding the functional mechanisms of such proteins requires the identification of the collective atomic motions and how these motions relate to the biological function. Methods. Molecular dynamics simulations are often used to complement the experimental studies as NMR, X-ray crystallography, single molecule fluorescence, electron transfer measurements and time resolved wide angle X-ray scattering, giving detailed information of atomic resolution about the collective atom motions. One method is especially used in this respect. The Principal Component Analysis (PCA) is based on the assumption that the vast majority of the protein dynamics can be described by a surprisingly low number of collective degrees of freedom. The dynamics of the low-dimensional subspace spanned by these modes was termed "Essential Dynamics" to reflect the fact that they are essential to the function. Results. In this study, we have performed molecular dynamics (MD) simulations of the catalytic domain of a known matrix metalloproteinase (MMP), in the absence of the substrate or a known inhibitor, starting from Protein DataBank published data (ID-1QIB). This study emphasizes the role of the atomic position in this site regarding to further simulations for conceiving a rather modulating inhibitor for these enzymes. The differences in the dynamic behavior of the protein induced by water molecules access in the catalytic site are discussed at the molecular level. Conclusions. The study focuses mainly on PCA analysis of the MMP but we are also studying the secondary structure conservation, root mean square deviation (RMSD) and fluctuation cluster analysis for a full structured description of the crystal structure of the MMP catalytic site. Based on the obtained results, we can thus define new tricks for strategies regarding MMP inhibitors design.