Optical Kerr Effect In Supercooled Water.

We present molecular dynamics simulations of the optical Kerr effect in liquid and supercooled water and compare with recent time-resolved Kerr spectroscopy measurements [R. Torre, Nature (London) 428, 296 (2004)]. The short time features of the Kerr response, characterized by peaks near 15, 60, and 160 fs, are weakly temperature dependent. The long-time decay is well described by a stretched exponential with a nearly constant stretch parameter and relaxation times that follow a power law approximately (T-T(S))(-gamma), with T(S)=198.3 K and gamma=2.35. Our findings are discussed in the light of the spectroscopy data and previous simulation analyzes of the structural relaxation in supercooled water.9413780

A review on the dynamics of water

We present a review on the intermolecular dynamics of liquid aqueous systems focusing mainly on Molecular Dynamics simulation work that has been carried out at the State University of Campinas in recent years. Emphasis is given on simulation results that are more directly related to modern experimental spectroscopic measurements.316Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Molecular dynamics simulations of the dielectric properties of fructose aqueous solutions

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)The static dielectric permittivity and dielectric relaxation properties of fructose aqueous solutions of different concentrations ranging from 1.0 to 4.0 mol l(-1) are investigated by means of molecular dynamics simulations. The contributions from intra-and interspecies molecular correlations were computed individually for both the static and frequency-dependent dielectric properties, and the results were compared with the available experimental data. Simulation results in the time- and frequency-domains were analyzed and indicate that the presence of fructose has little effect on the position of the fast, high-frequency (> 500 cm(-1)) components of the dielectric response spectrum. The low-frequency (< 0.1 cm(-1)) components, however, are markedly influenced by sugar concentration. Our analysis indicates that fructose-fructose and fructose-water interactions strongly affect the rotational-diffusion regime of molecular motions in the solutions. Increasing fructose concentration not only enhances sugar-sugar and sugar-water low frequency contributions to the dielectric loss spectrum but also slows down the reorientational dynamics of water molecules. These results are consistent with previous computer simulations carried out for other disaccharide aqueous solutions.The static dielectric permittivity and dielectric relaxation properties of fructose aqueous solutions of different concentrations ranging from 1.0 to 4.0 mol l−1 are investigated by means of molecular dynamics simulations. The contributions from intra- an2841FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)2013/08293-7This work has been funded by the Sao Paulo Research Foundation, FAPESP (Cepid grant #2013/08293-7

Ligand dissociation from estrogen receptor is mediated by receptor dimerization: Evidence from molecular dynamics simulations

Estrogen Receptor (ER) is an important target for pharmaceutical design. Like other ligand-dependent transcription factors, hormone binding regulates ER transcriptional activity. Nevertheless, the mechanisms by which ligands enter and leave ERs and other nuclear receptors remain poorly understood. Here, we report results of locally enhanced sampling molecular dynamics simulations to identify dissociation pathways of two ER ligands [the natural hormone 17 beta-estradiol (E-2) and the selective ER modulator raloxifene (RAL)] from the human ER alpha ligand-binding domain in monomeric and dimeric forms. E-2 dissociation occurs via three different pathways in ER monomers. One resembles the mousetrap mechanism (Path I), involving repositioning of helix 12 (H12), others involve the separation of H8 and H11 (Path II), and a variant of this pathway at the bottom of the ligand-binding domain (Path II`). RAL leaves the receptor through Path I and a Path I variant in which the ligand leaves the receptor through the loop region between H11 and H12 (Path I`). Remarkably, ER dimerization strongly suppresses Paths II and II` for E-2 dissociation and modifies RAL escape routes. We propose that differences in ligand release pathways detected in the simulations for ER monomers and dimers provide an explanation for previously observed effects of ER quaternary state on ligand dissociation rates and suggest that dimerization may play an important, and hitherto unexpected, role in regulation of ligand dissociation rates throughout the nuclear receptor family

Molecular Dynamics Simulations Reveal Multiple Pathways of Ligand Dissociation from Thyroid Hormone Receptors

Nuclear receptor (NR) ligands occupy a pocket that lies within the core of the NR ligand-binding domain (LBD), and most NR LBDs lack obvious entry/exit routes upon the protein surface. Thus, significant NR conformational rearrangements must accompany ligand binding and release. The precise nature of these processes, however, remains poorly understood. Here, we utilize locally enhanced sampling (LES) molecular dynamics computer simulations to predict molecular motions of x-ray structures of thyroid hormone receptor (TR) LBDs and determine events that permit ligand escape. We find that the natural ligand 3,5,3′-triiodo-L-thyronine (T(3)) dissociates from the TRα1 LBD along three competing pathways generated through i), opening of helix (H) 12; ii), separation of H8 and H11 and the Ω-loop between H2 and H3; and iii), opening of H2 and H3, and the intervening β-strand. Similar pathways are involved in dissociation of T(3) and the TRβ-selective ligand GC24 from TRβ; the TR agonist IH5 from the α- and β-TR forms; and Triac from two natural human TRβ mutants, A317T and A234T, but are detected with different frequencies in simulations performed with the different structures. Path I was previously suggested to represent a major pathway for NR ligand dissociation. We propose here that Paths II and III are also likely ligand escape routes for TRs and other NRs. We also propose that different escape paths are preferred in different situations, implying that it will be possible to design NR ligands that only associate stably with their cognate receptors in specific cellular contexts