TY - JOUR
T1 - Exploration of human serum albumin binding sites by docking and molecular dynamics flexible ligand - Protein interactions
AU - Deeb, Omar
AU - Rosales-Hernández, Martha Cecilia
AU - Gómez-Castro, Carlos
AU - Garduño-Juárez, Ramón
AU - Correa-Basurto, José
PY - 2010
Y1 - 2010
N2 - Five-nanosecond molecular dynamics (MD) simulations were performed on human serum albumin (HSA) to study the conformational features of its primary ligand binding sites (I and II). Additionally, 11 HSA snapshots were extracted every 0.5 ns to explore the binding affinity (Kd) of 94 known HSA binding drugs using a blind docking procedure. MD simulations indicate that there is considerable flexibility for the protein, including the known sites I and II. Movements at HSA sites I and II were evidenced by structural analyses and docking simulations. The latter enabled the study and analysis of the HSA-ligand interactions of warfarin and ketoprofen (ligands binding to sites I and II, respectively) in greater detail. Our results indicate that the free energy values by docking (Kd observed) depend upon the conformations of both HSA and the ligand. The 94 HSA-ligand binding Kd values, obtained by the docking procedure, were subjected to a quantitative structure-activity relationship (QSAR) study by multiple regression analysis. The best correlation between the observed and QSAR theoretical (Kd predicted) data was displayed at 2.5 ns. This study provides evidence that HSA binding sites I and II interact specifically with a variety of compounds through conformational adjustments of the protein structure in conjunction with ligand conformational adaptation to these sites. These results serve to explain the high ligand-promiscuity of HSA.
AB - Five-nanosecond molecular dynamics (MD) simulations were performed on human serum albumin (HSA) to study the conformational features of its primary ligand binding sites (I and II). Additionally, 11 HSA snapshots were extracted every 0.5 ns to explore the binding affinity (Kd) of 94 known HSA binding drugs using a blind docking procedure. MD simulations indicate that there is considerable flexibility for the protein, including the known sites I and II. Movements at HSA sites I and II were evidenced by structural analyses and docking simulations. The latter enabled the study and analysis of the HSA-ligand interactions of warfarin and ketoprofen (ligands binding to sites I and II, respectively) in greater detail. Our results indicate that the free energy values by docking (Kd observed) depend upon the conformations of both HSA and the ligand. The 94 HSA-ligand binding Kd values, obtained by the docking procedure, were subjected to a quantitative structure-activity relationship (QSAR) study by multiple regression analysis. The best correlation between the observed and QSAR theoretical (Kd predicted) data was displayed at 2.5 ns. This study provides evidence that HSA binding sites I and II interact specifically with a variety of compounds through conformational adjustments of the protein structure in conjunction with ligand conformational adaptation to these sites. These results serve to explain the high ligand-promiscuity of HSA.
KW - Docking
KW - Human serum albumin
KW - Molecular dynamics
KW - Multiple linear regression analysis
UR - http://www.scopus.com/inward/record.url?scp=73649138207&partnerID=8YFLogxK
U2 - 10.1002/bip.21314
DO - 10.1002/bip.21314
M3 - Artículo
C2 - 19785033
SN - 0006-3525
VL - 93
SP - 161
EP - 170
JO - Biopolymers
JF - Biopolymers
IS - 2
ER -