Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical ...properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts.
A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop offers an insightful overview of the understanding of the mechanistic foundations of allostery, gained from computational and experimental analyses of real protein systems and model systems. Various practical applications are illustrated.
Methane hydrates have important industrial and climate implications, yet their formation via homogeneous nucleation under natural, moderate conditions is poorly understood. Obtaining such ...understanding could lead to improved control of crystallization, as well as insight into polymorph selection in general, but is hampered by limited experimental resolution. Direct molecular dynamics simulations using atomistic force fields could provide such insight, but are not feasible for moderate undercooling, due to the rare event nature of nucleation. Instead, we harvest ensembles of the rare unbiased nucleation trajectories by employing transition path sampling.We find that with decreasing undercooling the mechanism shifts from amorphous to crystalline polymorph formation. At intermediate temperature the 2 mechanisms compete. Reaction coordinate analysis reveals the amount of a specific methane cage type is crucial for crystallization, while irrelevant for amorphous solids. Polymorph selection is thus governed by kinetic accessibility of the correct cage type and, moreover, occurs at precritical nucleus sizes, apparently against Ostwald’s step rule. We argue that these results are still in line with classical nucleation theory. Our findings illuminate how selection between competing methane hydrate polymorphs occurs and might generalize to other hydrates and molecular crystal formation.
Nested Transition Path Sampling Bolhuis, Peter G; Csányi, Gábor
Physical review letters,
2018-Jun-22, Letnik:
120, Številka:
25
Journal Article
Recenzirano
Odprti dostop
We introduce a novel transition path (TPS) sampling scheme employing nested sampling. Analogous to how nested sampling explores the entire configurational phase space for atomistic systems, nested ...TPS samples the entire available trajectory space in one simulation. Thermodynamic and path observables can be constructed a posteriori for all temperatures simultaneously. We exploit this to compute the rate of rare processes at arbitrarily low temperature through the coupling to easily accessible rates at high temperature. We illustrate the method on several model systems.
We investigate the molecular mechanism of monomer addition to a growing amyloid fibril composed of the main amyloidogenic region from the insulin peptide hormone, the LVEALYL heptapeptide. Applying ...transition path sampling in combination with reaction coordinate analysis reveals that the transition from a docked peptide to a locked, fully incorporated peptide can occur in two ways. Both routes involve the formation of backbone hydrogen bonds between the three central amino acids of the attaching peptide and the fibril, as well as a reorientation of the central Glu side chain of the locking peptide toward the interface between two β-sheets forming the fibril. The mechanisms differ in the sequence of events. We also conclude that proper docking is important for correct alignment of the peptide with the fibril, as alternative pathways result in misfolding.
For the homogeneous crystal nucleation process in a soft-core colloid model, we identify optimal reaction coordinates from a set of novel order parameters based on the local structure within the ...nucleus, by employing transition path sampling techniques combined with a likelihood maximization of the committor function. We find that nucleation is governed by solid clusters that consist of an hcp core embedded within a cloud of surface particles that are highly correlated with their nearest neighbors but not ordered in a high-symmetry crystal structure. The results shed new light on the interpretation of the surface and volume terms in classical nucleation theory.
Using Brownian dynamics simulations, we systematically study the effective interaction between two parallel hard walls in a 2D suspension of self-propelled (active) colloidal hard spheres, and we ...find that the effective force between two hard walls can be tuned from a long range repulsion into a long range attraction by changing the density of active particles. At relatively high densities, the active hard spheres can form a dynamic crystalline bridge, which induces a strong oscillating long range dynamic wetting repulsion between the walls. With decreasing density, the dynamic bridge gradually breaks, and an intriguing long range dynamic depletion attraction arises. A similar effect occurs in a quasi-2D suspension of self-propelled colloidal hard spheres by changing the height of the confinement. Our results open up new possibilities to manipulate the motion and assembly of microscopic objects by using active matter.
Dynamical reweighting techniques aim to recover the correct molecular dynamics from a simulation at a modified potential energy surface. They are important for unbiasing enhanced sampling simulations ...of molecular rare events. Here, we review the theoretical frameworks of dynamical reweighting for modified potentials. Based on an overview of kinetic models with increasing level of detail, we discuss techniques to reweight two-state dynamics, multistate dynamics, and path integrals. We explore the natural link to transition path sampling and how the effect of nonequilibrium forces can be reweighted. We end by providing an outlook on how dynamical reweighting integrates with techniques for optimizing collective variables and with modern potential energy surfaces.
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