RESUMO
In the Hamiltonian adaptive resolution simulation method (H-AdResS) it is possible to simulate coexisting atomistic (AT) and ideal gas representations of a physical system that belong to different subdomains within the simulation box. The Hamiltonian includes a field that bridges both models by smoothly switching on (off) the intermolecular potential as particles enter (leave) the AT region. In practice, external one-body forces are calculated and applied to enforce a reference density throughout the simulation box, and the resulting external potential adds up to the Hamiltonian. This procedure suggests an apparent dependence of the final Hamiltonian on the system's thermodynamic state that challenges the method's statistical mechanics consistency. In this paper, we explicitly include an external potential that depends on the switching function. Hence, we build a grand canonical potential for this inhomogeneous system to find the equivalence between H-AdResS and density functional theory (DFT). We thus verify that the external potential inducing a constant density profile is equal to the system's excess chemical potential. Given DFT's one-to-one correspondence between external potential and equilibrium density, we find that a Hamiltonian description of the system is compatible with the numerical implementation based on enforcing the reference density across the simulation box. In the second part of the manuscript, we focus on assessing our approach's convergence and computing efficiency concerning various model parameters, including sample size and solute concentrations. To this aim, we compute the excess chemical potential of water, aqueous urea solutions and Lennard-Jones (LJ) mixtures. The results' convergence and accuracy are convincing in all cases, thus emphasising the method's robustness and capabilities.
RESUMO
Here, we report the immunomodulating potential of N-palmitoyl-amino-ethyl-rigin amide (PR) and N-cholestanyl-amino-ethyl-rigin amide (CR), the two new structural analogs of rigin (an IgG-derived tetrapeptide). Their activity profiles are compared with native tuftsin (NT) and/or N-palmitoyl-amino-ethyl-tuftsin amide (PT) taken as positive control. To explore the possibility of their use as targeting molecules, they are incorporated into the liposome bilayer and, subsequently, interacted with macrophages in an in vitro study. The new analogs of rigin with the hydrophobicity introduced at the C-terminus are found to considerably improve both the cell-mediated and the humoral immune responses in mice. However, unlike tuftsin and its analog, which mainly activate polymorphonuclear leukocytes and macrophages, the rigin analogs appear to manifest their response more through lymphocytes. When administered prophylactically to a group of mice, at the dose of 100 micrograms/0.5 ml/mouse/day for 2 days (i.v.), followed by a challenge presented with 1 x 10(6) rbcs parasitised with Plasmodium berghei on day 0, substantial reduction in parasitaemia and rate of mortality is observed. This led to increase the median survival time (MST) of the treated group in comparison to the control group. The response is found to be more prominent in CR-treated mice possibly because of the presence of steroid moiety, which is likely to have more productive interaction with cell membranes. Incorporation of these peptides into the bilayer of liposomes does not alter the permeability behavior of vesicles and, in fact, enhances their uptake by the macrophages in an in vitro study. The effect, however, is dependent on both, the concentration of peptide liposomes and the time of incubation. Present study, thus, establishes the possible use of these analogs not only as adjuvant in chemotherapy, but also as a prophylactic supplement to boost the natural immune status. The activity response of rigin analogs is manifested through lymphocytes, they can also find use in the chemotherapy of diseases, like leishmaniasis, tuberculosis and leprosy, where macrophage activity is either tamed or impaired by pathogens.