Autor: |
Ghanakota P; Department of Medicinal Chemistry, College of Pharmacy , University of Michigan , 428 Church Street , Ann Arbor , Michigan 48109-1065 , United States., DasGupta D; Department of Medicinal Chemistry, College of Pharmacy , University of Michigan , 428 Church Street , Ann Arbor , Michigan 48109-1065 , United States., Carlson HA; Department of Medicinal Chemistry, College of Pharmacy , University of Michigan , 428 Church Street , Ann Arbor , Michigan 48109-1065 , United States. |
Jazyk: |
angličtina |
Zdroj: |
Journal of chemical information and modeling [J Chem Inf Model] 2019 May 28; Vol. 59 (5), pp. 2035-2045. Date of Electronic Publication: 2019 May 02. |
DOI: |
10.1021/acs.jcim.8b00925 |
Abstrakt: |
In our recent efforts to map protein surfaces using mixed-solvent molecular dynamics (MixMD) (Ghanakota, P.; Carlson, H. A. Moving Beyond Active-Site Detection: MixMD Applied to Allosteric Systems. J. Phys. Chem. B 2016, 120, 8685-8695), we were able to successfully capture active sites and allosteric sites within the top-four most occupied hotspots. In this study, we describe our approach for estimating the thermodynamic profile of the binding sites identified by MixMD. First, we establish a framework for calculating free energies from MixMD simulations, and we compare our approach to alternative methods. Second, we present a means to obtain a relative ranking of the binding sites by their configurational entropy. The theoretical maximum and minimum free energy and entropy values achievable under such a framework along with the limitations of the techniques are discussed. Using this approach, the free energy and relative entropy ranking of the top-four MixMD binding sites were computed and analyzed across our allosteric protein targets: Abl Kinase, Androgen Receptor, Pdk1 Kinase, Farnesyl Pyrophosphate Synthase, Chk1 Kinase, Glucokinase, and Protein Tyrosine Phosphatase 1B. |
Databáze: |
MEDLINE |
Externí odkaz: |
|