Towards accurate solvation free energies of large biological systems

Continuum solvation models like PCM or COSMO are the standard tool to calculate solvation free energies in a quantum level, but have been typically limited to small biological molecules due to its large computational cost. Recently, a new implementation of COSMO based on a domain decomposition strategy (ddCOSMO) [1] has been presented, which speeds up calculations by several orders of magnitude, thus paving the way for its application to very large systems. Here, we report the parameterization of ddCOSMO to the prediction of hydration free energies based on the MST solvation model developed in Barcelona, [2][3]. The parameterization is based on the PM6 semi-empirical Hamiltonian, on a set of over 200 experimental hydration free energies. The new model opens the way to the accurate prediction of hydration free energies of very large biomolecules, thus going beyond the usual classical MM-PBSA or MM-GBSA approaches

Infection by the hepatitis C virus in chronic renal failure patients undergoing hemodialysis in Mato Grosso state, central Brazil: a cohort study

BACKGROUND: Hepatitis C virus (HCV) is a significant problem for patients undergoing hemodialysis therapy. This situation has never been studied in Mato Grosso state, central Brazil. This study was conducted aiming to estimate the prevalence of the anti-HCV and the incidence of seroconversion in the main metropolitan region of the state. METHODS: 433 patients from the six hemodialysis units were interviewed and anti-HCV was tested by a third-generation enzyme immunoassay. An open cohort of patients who tested negative for anti-HCV at the entry of the study was created and seroconversions was assessed monthly. The staff responsible for the units were interviewed to assess whether the infection control measures were being followed. Logistic and Cox regression analysis were performed in order to assess risk factor to HCV. RESULTS: The entry on the study took place between January 2002 and June 2005. 73 out of 433 (16.9%, CI95%: 13.3–20.8) was found to be anti-HCV reactive. The multivariate analysis indicated as risk factors associated to anti-HCV the duration of the hemodialysis treatment, the number of transfusions received, and the unit of treatment. An open cohort of 360 patients who tested negative for anti-HCV was created, with a following average of 24 (± 15) months. Forty seroconversions were recorded corresponding to an incidence density of 4.6/1000 patient-months, ranges 0 to 30 among the units. Cox regression indicated the time of hemodialysis (RR = 2.2; CI95%: 1.1–4.6; p < 0.05) and the unit where treatment was performed (RR = 42.4; CI95%: 9.9–180.5; p < 0.05) as risk factors for seroconversion. The three units with highest anti-HCV prevalence and incidence were identified as those that more frequently failed to apply control measures. CONCLUSION: The study demonstrated high prevalence and incidence of anti-HCV in some of the hemodialysis units. Time on hemodialysis therapy was an independent factor associated to HCV. Blood transfusion was associated with anti-HCV in initial survey but was not important in incident cases. Failure of applying control meaures was more evident in units with the highest HCV prevalence and incidence. The results suggest that nosocomial transmission was the main spread factor of HCV in the studied population

Thermodynamics of Aryl-Dihydroxyphenyl-Thiadiazole Binding to Human Hsp90

The design of specific inhibitors against the Hsp90 chaperone and other enzyme relies on the detailed and correct understanding of both the thermodynamics of inhibitor binding and the structural features of the protein-inhibitor complex. Here we present a detailed thermodynamic study of binding of aryl-dihydroxyphenyl-thiadiazole inhibitor series to recombinant human Hsp90 alpha isozyme. The inhibitors are highly potent, with the intrinsic Kd approximately equal to 1 nM as determined by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). Dissection of protonation contributions yielded the intrinsic thermodynamic parameters of binding, such as enthalpy, entropy, Gibbs free energy, and the heat capacity. The differences in binding thermodynamic parameters between the series of inhibitors revealed contributions of the functional groups, thus providing insight into molecular reasons for improved or diminished binding efficiency. The inhibitor binding to Hsp90 alpha primarily depended on a large favorable enthalpic contribution combined with the smaller favorable entropic contribution, thus suggesting that their binding was both enthalpically and entropically optimized. The enthalpy-entropy compensation phenomenon was highly evident when comparing the inhibitor binding enthalpies and entropies. This study illustrates how detailed thermodynamic analysis helps to understand energetic reasons for the binding efficiency and develop more potent inhibitors that could be applied for therapeutic use as Hsp90 inhibitors

Predictive Power of Molecular Dynamics Receptor Structures in Virtual Screening

Molecular dynamics (MD) simulation is a well-established method for understanding protein dynamics. Conformations from unrestrained MD simulations have yet to be assessed for blind virtual screening (VS) by docking. This study presents a critical analysis of the predictive power of MD snapshots to this regard, evaluating two well-characterized systems of varying flexibility in ligand-bound and unbound configurations. Results from such VS predictions are discussed with respect to experimentally determined structures. In all cases, MD simulations provide snapshots that improve VS predictive power over known crystal structures, possibly due to sampling more relevant receptor conformations. Additionally, MD can move conformations previously not amenable to docking into the predictive range

Modeling Signal Propagation Mechanisms and Ligand-Based Conformational Dynamics of the Hsp90 Molecular Chaperone Full-Length Dimer

Hsp90 is a molecular chaperone essential for protein folding and activation in normal homeostasis and stress response. ATP binding and hydrolysis facilitate Hsp90 conformational changes required for client activation. Hsp90 plays an important role in disease states, particularly in cancer, where chaperoning of the mutated and overexpressed oncoproteins is important for function. Recent studies have illuminated mechanisms related to the chaperone function. However, an atomic resolution view of Hsp90 conformational dynamics, determined by the presence of different binding partners, is critical to define communication pathways between remote residues in different domains intimately affecting the chaperone cycle. Here, we present a computational analysis of signal propagation and long-range communication pathways in Hsp90. We carried out molecular dynamics simulations of the full-length Hsp90 dimer, combined with essential dynamics, correlation analysis, and a signal propagation model. All-atom MD simulations with timescales of 70 ns have been performed for complexes with the natural substrates ATP and ADP and for the unliganded dimer. We elucidate the mechanisms of signal propagation and determine “hot spots” involved in interdomain communication pathways from the nucleotide-binding site to the C-terminal domain interface. A comprehensive computational analysis of the Hsp90 communication pathways and dynamics at atomic resolution has revealed the role of the nucleotide in effecting conformational changes, elucidating the mechanisms of signal propagation. Functionally important residues and secondary structure elements emerge as effective mediators of communication between the nucleotide-binding site and the C-terminal interface. Furthermore, we show that specific interdomain signal propagation pathways may be activated as a function of the ligand. Our results support a “conformational selection model” of the Hsp90 mechanism, whereby the protein may exist in a dynamic equilibrium between different conformational states available on the energy landscape and binding of a specific partner can bias the equilibrium toward functionally relevant complexes

Wear and corrosion interactions on titanium in oral environment : literature review

The oral cavity is a complex environment where corrosive substances from dietary, human saliva, and oral biofilms may accumulate in retentive areas of dental implant systems and prostheses promoting corrosion at their surfaces. Additionally, during mastication, micromovements may occur between prosthetic joints causing a relative motion between contacting surfaces, leading to wear. Both processes (wear and corrosion) result in a bio-tribocorrosion system once that occurs in contact with biological tissues and fluids. This review paper is focused on the aspects related to the corrosion and wear behavior of titanium-based structures in the oral environment. Furthermore, the clinical relevance of the oral environment is focused on the harmful effect that acidic substances and biofilms, formed in human saliva, may have on titanium surfaces. In fact, a progressive degradation of titanium by wear and corrosion (tribocorrosion) mechanisms can take place affecting the performance of titanium-based implant and prostheses. Also, the formation of wear debris and metallic ions due to the tribocorrosion phenomena can become toxic for human tissues. This review gathers knowledge from areas like materials sciences, microbiology, and dentistry contributing to a better understanding of bio-tribocorrosion processes in the oral environment.(undefined