Summary Discrete molecular dynamics (DMD) is a rapid sampling method used in protein folding and aggregation studies. Until now, DMD was used to perform simulations of simplified protein models in conjunction with structure-based force fields. Here, we develop an all-atom protein model and a transferable force field featuring packing, solvation, and environment-dependent hydrogen bond interactions. Using the replica exchange method, we perform folding simulations of six small proteins (20–60 residues) with distinct native structures. In all cases, native or near-native states are reached in simulations. For three small proteins, multiple folding transitions are observed and the computationally-characterized thermodynamics are in quantitative agreement with experiments. The predictive power of all-atom DMD highlights the importance of environment-dependent hydrogen bond interactions in modeling protein folding. The developed approach can be used for accurate and rapid sampling of conformational spaces of proteins and protein-protein complexes, and applied to protein engineering and design of protein-protein interactions.

Low-level cumulative exposure to lead in nonoccupational settings may adversely affect cognitive function, particularly in the visuospatial/visuomotor domain.

BackgroundResearch using reconstructed exposure histories has suggested an association between heavy metal exposures, including lead, and Parkinson’s disease (PD), but the only study that used bone lead, a biomarker of cumulative lead exposure, found a nonsignificant increase in risk of PD with increasing bone lead.ObjectivesWe sought to assess the association between bone lead and PD.MethodsBone lead concentrations were measured using 109Cd excited K-shell X-ray fluorescence from 330 PD patients (216 men, 114 women) and 308 controls (172 men, 136 women) recruited from four clinics for movement disorders and general-community cohorts. Adjusted odds ratios (ORs) for PD were calculated using logistic regression.ResultsThe average age of cases and controls at bone lead measurement was 67 (SD = 10) and 69 (SD = 9) years of age, respectively. In primary analyses of cases and controls recruited from the same groups, compared with the lowest quartile of tibia lead, the OR for PD in the highest quartile was 3.21 [95% confidence interval (CI), 1.17–8.83]. Results were similar but slightly weaker in analyses restricted to cases and controls recruited from the movement disorders clinics only (fourth-quartile OR = 2.57; 95% CI, 1.11–5.93) or when we included controls recruited from sites that did not also contribute cases (fourth-quartile OR = 1.91; 95% CI, 1.01–3.60). We found no association with patella bone lead.ConclusionsThese findings, using an objective biological marker of cumulative lead exposure among typical PD patients seen in our movement disorders clinics, strengthen the evidence that cumulative exposure to lead increases the risk of PD.

Background— Blood lead concentration has been associated with mortality from different causes in several studies. Many effects of lead exposure that might increase risk of death are likely to result from cumulative exposure, for which bone lead is a better biomarker than blood lead. The association between bone lead levels and mortality has not been explored. Methods and Results— We prospectively assessed the association between both blood lead and bone lead, analyzed with the use of K-shell x-ray fluorescence, and mortality among 868 men in the Normative Aging Study. We identified 241 deaths over an average of 8.9 (SD=3.9) years of follow-up. We calculated adjusted hazard ratios and 95% confidence intervals using Cox proportional hazards. Compared with the lowest tertile of patella bone lead, the fully adjusted hazard ratios in the highest tertile for all-cause, cardiovascular (n=137 deaths), and ischemic heart disease (n=62 deaths) mortality were 1.25 (95% confidence interval, 0.82 to 1.92), 1.42 (95% confidence interval, 0.80 to 2.51), and 1.87 (95% confidence interval, 0.77 to 4.53), respectively. Results were similar for tibia lead. Bone lead was not associated with cancer, and blood lead was not associated with any mortality category. Conclusions— We found bone lead to be associated with a slight increase in all-cause and cardiovascular mortality in an environmentally exposed population with low blood lead levels, but this did not reach statistical significance. This study suggests that cumulative lead exposure from prior decades of high environmental exposures may affect risk of death despite recent declines in environmental lead exposure, but studies with more follow-up are needed.

BackgroundRecent data indicate that chronic low-level exposure to lead is associated with accelerated declines in cognition in older age, but this has not been examined in women.ObjectiveWe examined biomarkers of lead exposure in relation to performance on a battery of cognitive tests among older women.MethodsPatella and tibia bone lead—measures of cumulative exposure over many years—and blood lead, a measure of recent exposure, were assessed in 587 women 47–74 years of age. We assessed their cognitive function 5 years later using validated telephone interviews.ResultsMean ± SD lead levels in tibia, patella, and blood were 10.5 ± 9.7 μg/g bone, 12.6 ± 11.6 μg/g bone, and 2.9 ± 1.9 μg/dL, respectively, consistent with community-level exposures. In multivariable-adjusted analyses of all cognitive tests combined, levels of all three lead biomarkers were associated with worse cognitive performance. The association between bone lead and letter fluency score differed dramatically from the other bone lead-cognitive score associations, and exclusion of this particular score from the combined analyses strengthened the associations between bone lead and cognitive performance. Results were statistically significant only for tibia lead: one SD increase in tibia lead corresponded to a 0.051-unit lower standardized summary cognitive score (95% confidence interval: −0.099 to −0.003; p = 0.04), similar to the difference in cognitive scores we observed between women who were 3 years apart in age.ConclusionsThese findings suggest that cumulative exposure to lead, even at low levels experienced in community settings, may have adverse consequences for women’s cognition in older age.

Although lead has been associated with hearing loss in occupational settings and in children, little epidemiologic research has been conducted on the impact of cumulative lead exposure on age-related hearing loss in the general population. We determined whether bone lead levels, a marker of cumulative lead exposure, are associated with decreased hearing ability in 448 men from the Normative Aging Study, seen between 1962 and 1996 (2,264 total observations). Air conduction hearing thresholds were measured at 0.25 to 8 kHz and pure tone averages (PTA) (mean of 0.5, 1, 2 and 4 kHz) were computed. Tibia and patella lead levels were measured using K x-ray fluorescence between 1991 and 1996. In cross-sectional analyses, after adjusting for potential confounders including occupational noise, patella lead levels were significantly associated with poorer hearing thresholds at 2, 3, 4, 6 and 8 kHz and PTA. The odds of hearing loss significantly increased with patella lead levels. We also found significant positive associations between tibia lead and the rate change in hearing thresholds at 1, 2, and 8 kHz and PTA in longitudinal analyses. Our results suggest that chronic low-level lead exposure may be an important risk factor for age-related hearing loss and reduction of lead exposure could help prevent or delay development of age-related hearing loss.

Over the past three decades the protein folding field has undergone monumental changes. Originally a purely academic question, how a protein folds has now become vital in understanding diseases and our abilities to rationally manipulate cellular life by engineering protein folding pathways. We review and contrast past and recent developments in the protein folding field. Specifically, we discuss the progress in our understanding of protein folding thermodynamics and kinetics, the properties of evasive intermediates, and unfolded states. We also discuss how some abnormalities in protein folding lead to protein aggregation and human diseases.

BackgroundAltered heart rate variability (HRV), a marker of poor cardiac autonomic function, has been associated with sudden cardiac death and heart failure.ObjectiveWe examined the association of low-level lead exposure measured in bone by K-X-ray fluorescence with alterations in HRV, and whether metabolic syndrome (MetS) or its individual components modify those associations.MethodsHRV measures [power in high-frequency (HFnorm) and low-frequency (LFnorm) in normalized units, and LF/HF] were taken among 413 elderly men from the Normative Aging Study. MetS was defined as subjects having three or more of the following criteria: abdominal obesity, hypertriglyceridemia, low high-density lipoprotein, high blood pressure, and high fasting glucose.ResultsOf the subjects, 32% were identified as having MetS. Inverse but nonstatistically significant associations of both tibia and patella lead levels with HFnorm and nonstatistically significant positive relations with LFnorm and LF/HF were found in the entire cohort. There was a graded, statistically significant reduction in HFnorm and increases in LFnorm and LF/HF in association with an increase in patella lead as the number of metabolic abnormalities increased. We also observed that higher patella lead was consistently associated with lower HFnorm and higher LFnorm and LF/HF among subjects with MetS or its individual components. No statistically significant interaction between MetS and tibia lead was observed.ConclusionThe results suggest that elderly men with MetS were more susceptible to autonomic dysfunction in association with chronic lead exposure as measured in patella. The modification by MetS is consistent with a role for oxidative stress in lead toxicity on the cardiovascular system.