Single Proteoliposome High-Content Analysis Reveals Differences in the Homo-Oligomerization of GPCRs.

G-protein-coupled receptors (GPCRs) control vital cellular signaling pathways. GPCR oligomerization is proposed to increase signaling diversity. However, many reports have arrived at disparate conclusions regarding the existence, stability, and stoichiometry of GPCR oligomers, partly because of cellular complexity and ensemble averaging of intrareconstitution heterogeneities that complicate the interpretation of oligomerization data.

Big Data Analytic, Big Step for Patient Management and Care in Puerto Rico.

This letter provides an overview of the application of big data in health care system to improve quality of care, including predictive modelling for risk and resource use, precision medicine and clinical decision support, quality of care and performance measurement, public health and research applications, among others. The author delineates the tremendous potential for big data analytics and discuss how it can be successfully implemented in clinical practice, as an important component of a learning health-care system.

Optimizing transition interface sampling simulations.

We demonstrate that a recently proposed adaptive optimization algorithm for forward flux sampling simulations [E. E. Borrero and F.

Overcoming barriers in trajectory space: mechanism and kinetics of rare events via Wang-Landau enhanced transition path sampling.

Within the framework of transition path sampling (TPS), activation energies can be computed as path ensemble averages without a priori information about the reaction mechanism [C. Dellago and P. G.

Kinetics and mechanism of the unfolding native-to-loop transition of Trp-cage in explicit solvent via optimized forward flux sampling simulations.

The native-to-loop (N-L) unfolding transition of Trp-cage protein was studied via optimized forward flux sampling (FFS) methods with trajectories evolved using molecular dynamics. The rate constant calculated from our simulations is in good agreement with the experimental value for the native-to-unfolded transition of this protein; furthermore, the trajectories sampled a phase region consistent with that reported in previous studies for the N-L transition using transition path sampling and transition interface sampling. A new variant of FFS is proposed and implemented that allows a better control of a constant flux of partial paths.

Kinetics and reaction coordinates of the reassembly of protein fragments via forward flux sampling.

We studied the mechanism of the reassembly and folding process of two fragments of a split lattice protein by using forward flux sampling (FFS). Our results confirmed previous thermodynamics and kinetics analyses that suggested that the disruption of the critical core (of an unsplit protein that folds by a nucleation mechanism) plays a key role in the reassembly mechanism of the split system. For several split systems derived from a parent 48-mer model, we estimated the reaction coordinates in terms of collective variables by using the FFS least-square estimation method and found that the reassembly transition is best described by a combination of the total number of native contacts, the number of interchain native contacts, and the total conformational energy of the split system.

Transition path sampling and forward flux sampling. Applications to biological systems.

The last decade has seen a rapid growth in the number of simulation methods and applications dealing with the sampling of transition pathways of rare nanoscale events. Such studies are crucial, for example, for understanding the mechanism and kinetics of conformational transitions and enzymatic events associated with the function of biomolecules. In this review, a broad account of transition path sampling approaches is provided, starting from the general concepts, progressing to the specific principles that underlie some of the most important methods, and eventually singling out the so-called forward flux sampling method for a more detailed description.

Kinetics and reaction coordinate for the isomerization of alanine dipeptide by a forward flux sampling protocol.

Forward flux sampling (FFS) simulations were used to study the kinetics of alanine dipeptide both in vacuum and in explicit solvent. The recently proposed FFS least-squares estimation approach and an algorithm that optimizes the position of the interfaces were implemented to determine a reaction coordinate that adequately describes the transition dynamics. A new method is also introduced to try to ensure that the ensemble of "starting points" (for the trial trajectories) is properly sampled.

Simulating the kinetics and thermodynamics of transitions via forward flux/umbrella sampling.

First, a technique is introduced for computing equilibrium probability distributions for transitional rare-event simulations by combining the ensemble of trajectories generated by forward flux sampling (FFS) and by umbrella sampling (US) in multiple windows along an order parameter of interest; this method is denoted FFS-US. Second, the FFS algorithm is extended to obtain rate constants of partial transitions involving intermediate states from a single simulation; this is denoted "multiple state" FFS. For the FFS-US method, a FFS algorithm (preoptimized for order parameter and staging) is used to take advantage of its zero potential bias of phase-space sampling to gather histogram data with which to jump start the US and get the equilibrium distributions.

Optimizing the sampling and staging for simulations of rare events via forward flux sampling schemes.

In this work, we present an adaptive algorithm to optimize the phase space sampling for simulations of rare events in complex systems via forward flux sampling (FFS) schemes. In FFS, interfaces are used to partition the phase space along an order parameter lambda connecting the initial and final regions of interest. Since the kinetic "bottleneck" regions along the order parameter are not usually known beforehand, an adaptive procedure is used that first finds these regions by estimating the rate constants associated with reaching subsequent interfaces; thereafter, the FFS simulation is reset to concentrate the sampling on those bottlenecks.

Reaction coordinates and transition pathways of rare events via forward flux sampling.

A new approach is developed for identifying suitable reaction coordinates to describe the progression of rare events in complex systems. The method is based on the forward flux sampling (FFS) technique and standard least-square estimation (LSE) and it is denoted as FFS-LSE. The FFS algorithm generates trajectories for the transition between stable states as chains of partially connected paths, which can then be used to obtain "on-the-fly" estimates for the committor probability to the final region, p(B).

Folding kinetics of a lattice protein via a forward flux sampling approach.

We implement a forward flux sampling approach [R. J. Allen et al.