The kinetics of alpha-helix formation in polyalanine and polyglycine eicosamers (20-mers) were examined using torsional-coordinate molecular dynamics (MD). Of one hundred fifty-five MD experiments on extended (Ala)20 carried out for 0.5 ns each, 129 (83%) formed a persistent alpha-helix. In contrast, the extended state of (Gly)20 only formed a right-handed alpha-helix in two of the 20 MD experiments (10%), and these helices were not as long or as persistent as those of polyalanine. These simulations show helix formation to be a competition between the rates of (a) forming local hydrogen bonds (i.e. hydrogen bonds between any residue i and its i + 2, i + 3, i + 4, or i + 5th neighbor) and (b) forming nonlocal hydrogen bonds (HBs) between residues widely separated in sequence. Local HBs grow rapidly into an alpha-helix; but nonlocal HBs usually retard helix formation by "trapping" the polymer in irregular, "balled-up" structures. Most trajectories formed some nonlocal HBs, sometimes as many as eight. But, for (Ala)20, most of these eventually rearranged to form local HBs that lead to alpha-helices. A simple kinetic model describes the rate of converting nonlocal HBs into alpha-helices. Torsional-coordinate MD speeds folding by eliminating bond and angle degrees of freedom and reducing dynamical friction. Thus, the observed 210 ps half-life for helix formation is likely to be a lower bound on the real rate. However, we believe the sequential steps observed here mirror those of real systems.

The kinetics of alpha-helix formation in polyalanine and polyglycine eicosamers (20-mers) were examined using torsional-coordinate molecular dynamics (MD). Of one hundred fifty-five MD experiments on extended (Ala)20 carried out for 0.5 ns each, 129 (83%) formed a persistent alpha-helix. In contrast, the extended state of (Gly)20 only formed a right-handed alpha-helix in two of the 20 MD experiments (10%), and these helices were not as long or as persistent as those of polyalanine. These simulations show helix formation to be a competition between the rates of (a) forming local hydrogen bonds (i.e. hydrogen bonds between any residue i and its i + 2, i + 3, i + 4, or i + 5th neighbor) and (b) forming nonlocal hydrogen bonds (HBs) between residues widely separated in sequence. Local HBs grow rapidly into an alpha-helix; but nonlocal HBs usually retard helix formation by "trapping" the polymer in irregular, "balled-up" structures. Most trajectories formed some nonlocal HBs, sometimes as many as eight. But, for (Ala)20, most of these eventually rearranged to form local HBs that lead to alpha-helices. A simple kinetic model describes the rate of converting nonlocal HBs into alpha-helices. Torsional-coordinate MD speeds folding by eliminating bond and angle degrees of freedom and reducing dynamical friction. Thus, the observed 210 ps half-life for helix formation is likely to be a lower bound on the real rate. However, we believe the sequential steps observed here mirror those of real systems.

No abstract

No abstract

Introduction Tighter blood pressure control is widely thought to be associated with better erectile function, although the preponderance of data is limited to dichotomous representations of hypertension without an attempt to look at degree of blood pressure control. Aim To determine the association between optimal blood pressure control over time and the development of erectile dysfunction (ED) in a cohort of potent men. Methods We performed a retrospective cohort study of newly diagnosed hypertensive men without major medical comorbidities in an integrated healthcare system. Patients were stratified by exposure to hypertension, with varying levels of blood pressure control, as measured by ordinal categories of systolic blood pressure and deviation from the mean systolic pressure. Main Outcome Measures Incidence of ED was defined by at least 2 primary care or urology diagnoses of ED in our electronic health records within 2 years, at least 2 filled prescriptions for ED medications within 2 years, or 1 diagnosis of ED and 2 filled prescriptions for ED medications. Results We identified 39,320 newly diagnosed hypertensive men. The overall incidence for ED was 13.9%, with a mean follow-up of 55.1 ± 28.7 months. Higher average systolic blood pressure was associated with a higher risk of ED in a dose-dependent manner (trend test, P < .001). Wide variation in blood pressure control was associated with a higher incidence of ED (OR [95% CI]; 1.359 [1.258–1.469]) and a shorter time to the development of ED (log rank, P < .0001). Clinical Implications We believe these data may serve as a motivator for hypertensive men to better adhere to their hypertension treatment regimen. Strength & Limitations The retrospective nature of our study precludes us from drawing more than an association between tighter blood pressure control and ED. Strengths of our study include the large sample size, community cohort, and completeness of follow-up. Conclusion Among adults diagnosed with hypertension, tighter blood pressure control, as measured by average systolic blood pressure and deviation from the average, is associated with a lower incidence and a longer time to the development of ED.