Abstract
In this article, the Brownian dynamics fluctuation-dissipation theorem (BD-FDT) is applied to the study of transport of neutral solutes across the cellular membrane of Plasmodium berghei (Pb), a disease-causing parasite. Pb infects rodents and causes symptoms in laboratory mice that are comparable to human malaria caused by Plasmodium falciparum (Pf). Due to the relative ease of its genetic engineering, P. berghei has been exploited as a model organism for the study of human malaria. P. berghei expresses one type of aquaporin (AQP), PbAQP, and, in parallel, P. falciparum expresses PfAQP. Either PbAQP or PfAQP is a multifunctional channel protein in the plasma membrane of the rodent/human malarial parasite for homeostasis of water, uptake of glycerol, and excretion of some metabolic wastes across the cell membrane. This FDT-study of the channel protein PbAQP is to elucidate how and how strongly it interacts with water, glycerol, and erythritol. It is found that erythritol, which binds deep inside the conducting pore of PbAQP/PfAQP, inhibits the channel protein's functions of conducting water, glycerol etc. This points to the possibility that erythritol, a sugar substitute, may inhibit the malarial parasites in rodents and in humans.
Highlights
The fluctuation-dissipation theorem (FDT) is a corner stone of statistical mechanics
We present an atomistic computational study of P. berghei aquaglyceroporin (PbAQP) to elucidate how and how strongly this channel protein interacts with water, glycerol, erythritol etc
It is necessary and effective to map out the free energy profile in terms of the potential of mean force (PMF) that is defined as the Gibbs free energy of the entire system when a small number of degrees of freedom selected to characterize a process are located at a set of given values
Summary
The fluctuation-dissipation theorem (FDT) is a corner stone of statistical mechanics. FDT relates the dissipative characteristics of a nonequilibrium system (such as diffusivity for mass flux in response to a concentration gradient and conductivity for electric current in response an electric field) to the equilibrium fluctuations of the corresponding microscopic quantities (velocities and currents respectively). The former (diffusivity/conductivity) gives how a system responds to a perturbation imposed on the system while the latter represents the statistics of the microscopic quantities (velocities/currents) that constantly fluctuate even in an equilibrium state. The strategy of this study is to force/pull the relevant small molecules from the bound state to the apo state in all-atom simulations and quantify how the system respond to such imposed perturbations, from which the Gibbs free energies of binding will be extracted
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