Abstract

Protein kinases have become one of the principal targets in the drugs development in many pharmaceutical companies due to the critical role into intracellular signaling system. In response to growth factors, the protein kinases activate a several metabolic pathways, which generate cellular response such as mitogenesis, proliferation, differentiation, migration, or induction of apoptosis1-4. Many studies have focused on cancer because overexpression of protein kinases is frequently associated with many human cancers such as colon, pancreas, kidney, ovarian cancer and others2-5. Since PKA is involved in the intracellular signaling system, this must be specific and act at a specific target in the cell. This specificity is essential for cell integrity and depends on the complementarity between the kinase and its substrate, and therefore, its structure tridimencional5-8. The experimental methods for the identification and characterization of substrate specificity, are very expensive and laborious therefore computational studies are being developed to reduce the amount of experimental work 6,7, which, substrates of different sizes have been used to determine the influence of these on the phosphorylation. However, there do not exist in the literature theoretical studies aimed to explain the difference of affinity of different substrates by protein kinase A6, 7. In this work, we study the affinity of the peptide LRRASLG and several of its mutants through Molecular Dynamics simulation and MMGBSA (Molecular Mechanics-Generalized Born Surface Area). Preliminary results show that the RMSD (Root Means Square Displacements) was not greater than 1.5 Å for all systems, the largest displacement was for R18K mutant (1.18 Å) and the smallest displacement was of the R19K mutant (1.09 Å). MM-GBSA method shows that the Van der Waals interactions are the main contributors to the substrate-protein binding stability.