Accurate multiple time step in biased molecular simulations

Many recently introduced enhanced sampling techniques are based on biasing coarse descriptors (collective variables) of a molecular system on the fly. Sometimes the calculation of such collective variables is expensive and becomes a bottleneck in molecular dynamics simulations. An algorithm to treat smooth biasing forces within a multiple time step framework is here discussed. The implementation is simple and allows a speed up when expensive collective variables are employed. The gain can be substantial when using massively parallel or GPU-based molecular dynamics software. Moreover, a theoretical framework to assess the sampling accuracy is introduced, which can be used to assess the choice of the integration time step in both single and multiple time step biased simulations

Molecular Mapping of Sinoatrial Node HCN Channel Expression in the Human Heart.

BACKGROUND: The hyperpolarization-activated current, I(f), plays an important role in sinoatrial node (SAN) pacemaking. Surprisingly, the distribution of Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels in human SAN has only been investigated at the mRNA level. Our aim was to define the expression pattern of HCN proteins in human SAN and different atrial regions. METHODS AND RESULTS: Entire SAN complexes were isolated from failing (n=5) and non-failing (n=9) human hearts cardioplegically-arrested in the operating room. Three dimensional intramural SAN structure was identified as the fibrotic compact region around the SAN artery with Connexin43-negative pacemaker cardiomyocytes visualized in Masson’s trichrome and immunostained cryosections. SAN protein was precisely isolated from the adjacent frozen SAN tissue blocks using a 16G biopsy needle. The purity of the SAN protein was confirmed by Connexin43 immunoblot. All three HCN isoform proteins were detected in SAN. HCN1 was predominantly distributed in the human SAN with a 125.1±40.2 (n=12) expression ratio of SAN to right atrium (RA). HCN2 and HCN4 expression levels were higher in SAN than atria with SAN to RA ratios of 6.1±0.9 and 4.6±0.6 (n=12), respectively. CONCLUSIONS: This is the first study to conduct precise 3D molecular mapping of the human SAN by isolating pure pacemaker SAN tissue. All three cardiac HCN isoforms had higher expression in the SAN than the atria. HCN1 was almost exclusively expressed in SAN, emphasizing its utility as a new specific molecular marker of the human SAN and as a potential target of specific treatments intended to modify sinus rhythm