Molecular Dynamics Simulations of Protein-Ligand Complexes in Near Physiological Conditions




Wambo, Thierry Oscar

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Proteins are important molecules for their key functions. However, under certain circumstances, the function of these proteins needs to be regulated to keep us healthy. Ligands are small molecules often used to modulate the function of proteins. The binding affinity is a quantitative measure of how strong the ligand will modulate the function of the protein: a strong binding affinity will highly impact the performance of the protein. It becomes clear that it is critical to have appropriate techniques to accurately compute the binding affinity. The most difficult task in computer simulations is how to efficiently sample the space spanned by the ligand during the binding process. In this work, we have developed some schemes to compute the binding affinity of a ligand to a protein, and of a metal ion to a protein. Application of these techniques to some complexes yield results in agreement with experimental values. These methods are a brute force approach and make no assumption other than that the complexes are governed by the force field used. Specifically, we computed the free energy of binding between (1) human carbonic anhydrase II and the drug acetazolamide (hcaII-AZM), (2) human carbonic anhydrase II and the zinc ion (hcaII-Zinc), and (3) beta-lactoglobulin and five fatty acids complexes (BLG-FAs). We found the following free energies of binding in unit of kcal/mol: -12.96 ±2.44 (-15.74) for hcaII-Zinc complex, -5.76±0.76 (-5.57 ) for BLG-OCA , -4.44±1.08 (-5.22 ) for BLG-DKA,-6.89±1.25 (-7.24) for BLG-DAO, -8.57±0.82(-8.14) for BLG-MYR, -8.99±0.87(-8.72) for BLG-PLM, and -11.87±1.8 (-10.8 ) for hcaII-AZM. The values inside the parentheses are experimental results. The simulations and quantitative analysis of each system provide interesting insights into the interactions between each entity and helps us to better understand the dynamics of these systems.


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Physics and Astronomy