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We have performed molecular dynamics (MD) and replica-exchange (REMD) simulations of folding of the GB1 hairpin peptide in aqueous solution. REMD results were consistent with a cooperative zipper folding model. 120 μs MD trajectories at 320 K yielded relaxation times of 1.8 μs and 100 ns, with the slower assigned to global folding. The MD folding/unfolding transitions also followed the cooperative zipper model, specifying nucleation at the central turn followed by consecutive hydrogen bond formation. Formation of hydrogen bonds and hydrophobic contacts were highly correlated. Coarse-grained kinetic models constructed with the Optimal Dimensionality Reduction (ODR) approach found a folding time of 3.3 μs and unfolding time of 4.0 μs. Additionally, relaxation times in the 130–170 ns range could be assigned to formation of the transition state and off-path intermediates. The unfolded state was the most highly populated and, significantly, most heterogenous, assembling the largest number of microstates, primarily composed of extended and turn structures. The folded state was also heterogenous, but a to a lesser degree, involving the fully folded and partially folded in-register hairpins at early stages of the zipper pathway. The transition state corresponded to the nucleated hairpin, with central turn and first beta-sheet hydrogen bond, while the off-path intermediates were off-register partial hairpins. Our simulation results were in excellent agreement with experimental data on folded fraction, relaxation time and folding mechanism. The new findings from this work suggest a highly cooperative zipper folding mechanism, nascent hairpin transition state and ∼100 ns relaxation related to intermediate formation. Communicated by Ramaswamy H. Sarma

Acute kidney injury (AKI) is a common and serious condition that occurs in approximately 30% to 50% of pediatric patients that undergo cardiac surgery. Currently used parameters to measure kidney function (serum creatinine and urine output) are often unreliable and delay the prediction of AKI, despite their adoption into clinical guidelines. Emerging evidence suggests that biomarkers such as neutrophil gelatinase-associated lipocalin, cystatin C, interleukin-18, kidney injury molecule 1, and liver-type fatty acid– binding protein may be useful in the identification and location of pediatric renal injury. Ontogeny-related changes in tubular function and nephrogenesis result in reference values that differ based on age and sex. In addition, changes in endogenous concentrations may result from factors such as cardiopulmonary bypass. The use of urine samples to measure renal biomarkers offers a significant advantage compared with routine blood sampling, especially in the neonatal patient population. Future research is warranted to determine age-dependent changes in AKI biomarkers and the relationship with pharmacokinetic clearance of commonly used medications in the postoperative cardiac patient.