Solvent fluctuations induce non-Markovian kinetics in hydrophobic pocket-ligand binding

We investigate the impact of water fluctuations on the key-lock association kinetics of a hydrophobic ligand (key) binding to a hydrophobic pocket (lock) by means of a minimalistic stochastic model system. It describes the collective hydration behavior of the pocket by bimodal fluctuations of a water-pocket interface that dynamically couples to the diffusive motion of the approaching ligand via the hydrophobic interaction. This leads to a set of overdamped Langevin equations in 2D-coordinate-space, that is Markovian in each dimension. Numerical simulations demonstrate locally increased friction of the ligand, decelerated binding kinetics, and local non-Markovian (memory) effects in the ligand's reaction coordinate as found previously in explicit-water molecular dynamics studies of model hydrophobic pocket-ligand binding [1,2]. Our minimalistic model elucidates the origin of effectively enhanced friction in the process that can be traced back to long-time decays in the force-autocorrelation function induced by the effective, spatially fluctuating pocket-ligand interaction. Furthermore, we construct a generalized 1D-Langevin description including a spatially local memory function that enables further interpretation and a semi-analytical quantification of the results of the coupled 2D-system

Dewetting-controlled binding of ligands to hydrophobic pockets

We report on a combined atomistic molecular dynamics simulation and implicit solvent analysis of a generic hydrophobic pocket-ligand (host-guest) system. The approaching ligand induces complex wetting/dewetting transitions in the weakly solvated pocket. The transitions lead to bimodal solvent fluctuations which govern magnitude and range of the pocket-ligand attraction. A recently developed implicit water model, based on the minimization of a geometric functional, captures the sensitive aqueous interface response to the concave-convex pocket-ligand configuration semi-quantitatively

Charged N-terminus of Influenza Fusion Peptide Facilitates Membrane Fusion

Cleavage of hemagglutinin precursor (HA0) by cellular proteases results in the formation of two subunits, HA1 and HA2. The N-terminal fragment of HA2, named a fusion peptide (HAfp), possess a charged, amine N-terminus. It has been shown that the N-terminus of HAfp stabilizes the structure of a helical hairpin observed for a 23-amino acid long peptide (HAfp1-23), whose larger activity than HAfp1-20 has been demonstrated recently. In this paper, we analyze the effect of N-terminal charge on peptide-mediated fusion efficiency and conformation changes at the membrane interface by comparison with the corresponding N-acetylated peptides of 20- and 23-amino acid lengths. We found that higher fusogenic activities of peptides with unmodified amino termini correlates with their ability to form helical hairpin structures oriented perpendicularly to the membrane plane. Molecular dynamics simulations showed that acetylated peptides adopt open and surface-bound conformation more often, which induced less disorder of the phospholipid chains, as compared to species with unmodified amino termini

Treatment goal attainment for secondary prevention in coronary patients with or without diabetes mellitus : Polish multicenter study POLASPIRE

Introduction: Cardiovascular disease is still a leading cause of death in Poland and across Europe. The aim of this study was to assess the attainment of the main treatment goals for secondary cardiovascular prevention in coronary patients with or without diabetes mellitus (DM) in Poland. Material and methods: The study group included 1026 patients (65.5 ±9 y.o.; males: 72%) included at least 6 months after the index hospitalisation for myocardial infarction, unstable angina, elective percutaneous coronary intervention or coronary artery bypass surgery. The target and treatment goals were defined according to the 2016 European Society of Cardiology guidelines on cardiovascular prevention. Results: Patients with DM (n = 332; 32%) were slightly older compared to non-diabetic (n = 694) individuals (67.2 ±7 vs. 64.6 ±9 years old; p < 0.0001). The DM goal was achieved in 196 patients (60%). The rate of primary (LDL: 51% vs. 35%; p < 0.0001) and secondary (non-HDL: 56% vs. 48%; p < 0.02) goal attainment was higher in DM(+) compared to DM(–) patients. The rate of target blood pressure was lower in DM(+) than in normoglycemic patients (52% vs. 61% at < 140/90 mm Hg, p < 0.01. As expected, goal achievement of normal weight (9.5% vs. 19%; p < 0.0001) and waist circumference (7% vs. 15%; p < 0.001) was lower in diabetic patients and the rate of regular physical activity was similar (DM+ 12% vs. DM– 14%; p = ns). Finally, there was no difference in active smokers (DM+ 23% vs. DM– 22%; p = ns). Conclusions: Great majority of Polish patients in secondary prevention do not achieve treatment goals. Although lipid goals attainment is better in DM and the rate of smokers is similar, the management of all risk factors needs to be improved

Kamizelka defibrylująca w okresie poporodowym u pacjentki z kardiomiopatią

Cardiovascular diseases during pregnancy increase the risk of morbidity and mortality in pregnant women and their children. We present the case of a 37-year-old patient with cardiomyopathy who developed significant deterioration of left ventricular function accompanied by fetal death at 28 gestational week, and who was subsequently provided with a wearable cardioverter defibrillator as a part of sudden cardiac death prevention.Choroby układu sercowo-naczyniowego u kobiet w ciąży zwiększają ryzyko chorobowości i śmiertelności zarówno matek, jak i dzieci. W artykule przedstawiono przypadek 37-letniej pacjentki z kardiomiopatią, u której w 28. tygodniu ciąży doszło do znacznego pogorszenia funkcji lewej komory oraz obumarcia płodu i którą zaopatrzono kamizelką defibrylującą w ramach prewencji nagłego zgonu sercowego

Secondary prevention of coronary artery disease in Poland. Results from the POLASPIRE survey

Background: The highest priority in preventive cardiology is given to patients with established coronary artery disease (CAD). The aim of the study was to assess the current implementation of the guidelines for secondary prevention in everyday clinical practice by evaluating control of the main risk factors and the cardioprotective medication prescription rates in patients following hospitalization for CAD.Methods: Fourteen departments of cardiology participated in the study. Patients (aged ≤ 80 years) hospitalized due an acute coronary syndrome or for a myocardial revascularization procedure were recruited and interviewed 6–18 months after the hospitalization.Results: Overall, 947 patients were examined 6–18 months after hospitalization. The proportion of patientswith high blood pressure (≥ 140/90 mmHg) was 42%, with high low-density lipoprotein cholesterol (LDL-C ≥ 1.8 mmol/L) 62%, and with high fasting glucose (≥ 7.0 mmol/L) 22%, 17% of participants were smokers and 42% were obese. The proportion of patients taking an antiplatelet agent 6–18 months after hospitalization was 93%, beta-blocker 89%, angiotensin converting enzyme inhibitor or sartan 86%, and a lipid-lowering drug 90%. Only 2.3% patients had controlled all the five main risk factors well (non-smoking, blood pressure &lt; 140/90 mmHg, LDL-C &lt; 1.8 mmol/L and glucose &lt; 7.0 mmol/L, body mass index &lt; 25 kg/m2), while 17.9% had 1 out of 5, 40.9% had 2 out of 5, and 29% had 3 out of 5 risk factors uncontrolled.Conclusions: The documented multicenter survey provides evidence that there is considerable potential for further reductions of cardiovascular risk in CAD patients in Poland. A revision of the state funded cardiac prevention programs seems rational

Secondary prevention of coronary artery disease in Poland : results from the POLASPIRE survey

Background: The highest priority in preventive cardiology is given to patients with established coronary artery disease (CAD). The aim of the study was to assess the current implementation of the guidelines for secondary prevention in everyday clinical practice by evaluating control of the main risk factors and the cardioprotective medication prescription rates in patients following hospitalization for CAD. Methods: Fourteen departments of cardiology participated in the study. Patients (aged <= 80 years) hospitalized due an acute coronary syndrome or for a myocardial revascularization procedure were recruited and interviewed 6-18 months after the hospitalization. Results: Overall, 947 patients were examined 6-18 months after lwspitalization. The proportion of patients with high blood pressure (>= 140/90 mmHg) was 42%, with high low-density lipoprotein cholesterol (LDL-C >= 1.8 mmol/L) 62%, and with high fasting glucose (>= 7.0 mmol/L) 22%, 17% of participants were smokers and 42% were obese. The proportion of atients taking an antiplatelet agent 6-18 months after hospitalization was 93%, beta-blacker 89%, angiotensin converting enzyme inhibitor or sartan 86%, and a lipid-lowering drug 90%. Only 2.3% patients had controlled all the five main risk factors well (non-smoking, blood pressure < 140190 mmHg, LDL-C < 1.8 mmoIlL and glucose < 7.0 mmoilL, body mass index < 25 kg/m(2)), while 179% had 1 out of 5, 40.9% had 2 out of 5, and 29% had 3 out of 5 risk factors uncontrolled. Conclusions: The documented multicenter survey provides evidence that there is considerable potential for further reductions of cardiovascular risk in CAD patients in Poland. A revision of the state funded cardiac prevention programs seems rational

Water in Cavity−Ligand Recognition

We use explicit solvent molecular dynamics simulations to estimate free energy, enthalpy, and entropy changes along the cavity-ligand association coordinate for a set of seven model systems with varying physicochemical properties. Owing to the simplicity of the considered systems we can directly investigate the role of water thermodynamics in molecular recognition. A broad range of thermodynamic signatures is found in which water (rather than cavity or ligand) enthalpic or entropic contributions appear to drive cavity-ligand binding or rejection. The unprecedented, nanoscale picture of hydration thermodynamics can help the interpretation and design of protein-ligand binding experiments. Our study opens appealing perspectives to tackle the challenge of solvent entropy estimation in complex systems and for improving molecular simulation models

A coarse-grained force field for Protein–RNA docking

The awareness of important biological role played by functional, non coding (nc) RNA has grown tremendously in recent years. To perform their tasks, ncRNA molecules typically unite with protein partners, forming ribonucleoprotein complexes. Structural insight into their architectures can be greatly supplemented by computational docking techniques, as they provide means for the integration and refinement of experimental data that is often limited to fragments of larger assemblies or represents multiple levels of spatial resolution. Here, we present a coarse-grained force field for protein-RNA docking, implemented within the framework of the ATTRACT program. Complex structure prediction is based on energy minimization in rotational and translational degrees of freedom of binding partners, with possible extension to include structural flexibility. The coarse-grained representation allows for fast and efficient systematic docking search without any prior knowledge about complex geometry

SPOT-Seq-RNA: Predicting protein-RNA complex structure and RNA-binding function by fold recognition and binding affinity prediction

RNA-binding proteins (RBPs) play key roles in RNA metabolism and post-transcriptional regulation. Computational methods have been developed separately for prediction of RBPs and RNA-binding residues by machine-learning techniques and prediction of protein-RNA complex structures by rigid or semiflexible structure-to-structure docking. Here, we describe a template-based technique called SPOT-Seq-RNA that integrates prediction of RBPs, RNA-binding residues, and protein-RNA complex structures into a single package. This integration is achieved by combining template-based structure-prediction software, SPARKS X, with binding affinity prediction software, DRNA. This tool yields reasonable sensitivity (46 %) and high precision (84 %) for an independent test set of 215 RBPs and 5,766 non-RBPs. SPOT-Seq-RNA is computationally efficient for genome-scale prediction of RBPs and protein-RNA complex structures. Its application to human genome study has revealed a similar sensitivity and ability to uncover hundreds of novel RBPs beyond simple homology. The online server and downloadable version of SPOT-Seq-RNA are available at http://sparks-lab.org/server/SPOT-Seq-RNA/