MD Simulation of Protein-Ligand Interaction: Formation and Dissociation of an Insulin-Phenol Complex

Abstract

Complexes of proteins with small ligands are of utmost importance in biochemistry, and therefore equilibria, formation, and decay have been investigated extensively by means of biochemical and biophysical methods. Theoretical studies of the molecular dynamics of such systems in solution are restricted to 10 ns, i.e., to fast processes. Only recently new theoretical methods have been developed not to observe the process in real time, but to explore its pathway(s) through the energy landscape. From the profiles of free energy, equilibrium and kinetic quantities can be determined using transition-state theory. This study is dedicated to the pharmacologically relevant insulin-phenol complex. The distance of the center of mass chosen as a reaction coordinate allows a reasonable description over most of the pathway. The analysis is facilitated by analytical expressions we recently derived for distance-type reaction coordinates. Only the sudden onset of rotations at the very release of the ligand cannot be parameterized by a distance. They obviously require a particular treatment. Like a preliminary study on a peptide, the present case emphasizes the contribution of internal friction inside a protein, which can be computed from simulation data. The calculated equilibrium constant and the friction-corrected rates agree well with experimental data.

SEEKR: Simulation Enabled Estimation of Kinetic Rates, A Computational Tool to Estimate Molecular Kinetics and Its Application to Trypsin–Benzamidine Binding

“…The k on and k off relate to the dissociation constant K D , and by extension, a free energy of association Δ G bind : 6 …”

“…7 Additional clever methodologies can be used to speed the computation using MD. 6, 8, 23–25 Brownian dynamics (BD) can also be used to approach the problem of binding kinetics, 5, 26–29 as can Smoluchowski equation solvers. 30 …”

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“…The obtained average constraint forces from the simulations of the last 3 ns of the simulations where integrated and corrected for their entropic part to obtain the PMF corresponding to f R ¼ @U Swegat et al, 2003). The standard error Fig.…”

Three dimensional model of severe acute respiratory syndrome coronavirus helicase ATPase catalytic domain and molecular design of severe acute respiratory syndrome coronavirus helicase inhibitors

“…Recent developments in hybrid quantum mechanics (QM) and MM method created new opportunities in more accurate assessment of interaction energies [22][23][24][25]. In particular ONIOM method nicely resolved problems with QM and MM boundary and was successfully utilized in studies on mechanism of enzymatic reactions or calculations of interaction energies between proteins and their ligands [26][27][28][29][30][31].…”