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Dopamine transporter (DAT) and sigma‐1 receptor (σ1R) are potential therapeutic targets to reduce the psychostimulant effects induced by methamphetamine (METH). Interaction of σ1R with DAT could modulate the binding of METH, but the molecular basis of the association of the two transmembrane proteins and how their interactions mediate the binding of METH to DAT or σ1R remain unclear. Here, we characterize the protein–ligand and protein–protein interactions at a molecular level by various theoretical approaches. The present results show that METH adopts a different binding pose in the binding pocket of σ1R and is more likely to act as an agonist. The relatively lower binding affinity of METH to σ1R supports the role of antagonists as inhibitors that protect against METH‐induced effects. We demonstrate that σ1R could bind to Drosophila melanogaster DAT (dDAT) through interactions with either the transmembrane helix α12 or α5 of dDAT. Our results showed that the truncated σ1R displays stronger association with dDAT than the full‐length σ1R. Although different helix–helix interactions between σ1R and dDAT lead to distinct effects on the dynamics of individual protein, both associations attenuate the binding affinity of METH to dDAT, particularly in the interactions with the helix α5 of dDAT. Together, the present study provides the first computational investigation on the molecular mechanism of coupling METH binding and the association of σ1R with dDAT. [ABSTRACT FROM AUTHOR]

Glucose transporters (GLUTs), expressed in all types of human cells, are responsible for the uptake of sugars as the primary energy source for the normal functions of good cells and for the abnormal growth of cancer cells. The E. coli xylose permease (XylE), a homologue of human GLUTs, has been investigated more thoroughly than other major facilitator proteins in the current literature. In this paper, we present a molecular dynamics (MD) study of an all-atom model system to elucidate the atomistic details and the free-energy landscape along the path of binding a xylopyranose (XYP) from the extracellular space to the inside of the transporter protein XylE. From the MD simulations, the Gibbs free energy of binding was found to be − 4.4 kcal/mol in agreement with the experimental value of − 4.7 kcal/mol. The accuracy of our study is further shown in the computed hydration energy of XYP of − 14.6 kcal/mol in comparison with the experimental data of − 15.0 kcal/mol. Along the binding path, the Gibbs free energy of the XYP-XylE complex first rises from zero in the dissociated state to approximately 4 kcal/mol in the transition state (when XylE slightly increases its opening toward the extracellular side to accommodate XYP) before dropping down to − 9.0 kcal/mol in the bound state. These quantitative insights indicate the fast equilibration between the bound and the unbound states of XylE and XYP. They also serve as an atomistic-dynamic corroboration of the experimental conclusion that XylE is a high-affinity sugar transporter. [ABSTRACT FROM AUTHOR]

Computing the ligand-protein binding affinity (or the Gibbs free energy) with chemical accuracy has long been a challenge for which many methods/approaches have been developed and refined with various successful applications. False positives and, even more harmful, false negatives have been and still are a common occurrence in practical applications. Inevitable in all approaches are the errors in the force field parameters we obtain from quantum mechanical computation and/or empirical fittings for the intra- and inter-molecular interactions. These errors propagate to the final results of the computed binding affinities even if we were able to perfectly implement the statistical mechanics of all the processes relevant to a given problem. And they are actually amplified to various degrees even in the mature, sophisticated computational approaches. In particular, the free energy perturbation (alchemical) approaches amplify the errors in the force field parameters because they rely on extracting the small differences between similarly large numbers. In this paper, we develop a hybrid steered molecular dynamics (hSMD) approach to the difficult binding problems of a ligand buried deep inside a protein. Sampling the transition along a physical (not alchemical) dissociation path of opening up the binding cavity---pulling out the ligand---closing back the cavity, we can avoid the problem of error amplifications by not relying on small differences between similar numbers. We tested this new form of hSMD on retinol inside cellular retinol-binding protein 1 and three cases of a ligand (a benzylacetate, a 2-nitrothiophene, and a benzene) inside a T4 lysozyme L99A/M102Q(H) double mutant. In all cases, we obtained binding free energies in close agreement with the experimentally measured values. This indicates that the force field parameters we employed are accurate and that hSMD (a brute force, unsophisticated approach) is free from the problem of error amplification suffered by many sophisticated approaches in the literature. [ABSTRACT FROM AUTHOR]