Single-Sweep Methods for Free Energy Calculations

A simple, efficient, and accurate method is proposed to map multi-dimensional free energy landscapes. The method combines the temperature-accelerated molecular dynamics (TAMD) proposed in [Maragliano & Vanden-Eijnden, Chem. Phys. Lett. 426, 168 (2006)] with a variational reconstruction method using radial-basis functions for the representation of the free energy. TAMD is used to rapidly sweep through the important regions of the free energy landscape and compute the gradient of the free energy locally at points in these regions. The variational method is then used to reconstruct the free energy globally from the mean force at these points. The algorithmic aspects of the single-sweep method are explained in detail, and the method is tested on simple examples, compared to metadynamics, and finally used to compute the free energy of the solvated alanine dipeptide in two and four dihedral angles

Charting nanocluster structures via convolutional neural networks

A general method to obtain a representation of the structural landscape of nanoparticles in terms of a limited number of variables is proposed. The method is applied to a large dataset of parallel tempering molecular dynamics simulations of gold clusters of 90 and 147 atoms, silver clusters of 147 atoms, and copper clusters of 147 atoms, covering a plethora of structures and temperatures. The method leverages convolutional neural networks to learn the radial distribution functions of the nanoclusters and to distill a low-dimensional chart of the structural landscape. This strategy is found to give rise to a physically meaningful and differentiable mapping of the atom positions to a low-dimensional manifold, in which the main structural motifs are clearly discriminated and meaningfully ordered. Furthermore, unsupervised clustering on the low-dimensional data proved effective at further splitting the motifs into structural subfamilies characterized by very fine and physically relevant differences, such as the presence of specific punctual or planar defects or of atoms with particular coordination features. Owing to these peculiarities, the chart also enabled tracking of the complex structural evolution in a reactive trajectory. In addition to visualization and analysis of complex structural landscapes, the presented approach offers a general, low-dimensional set of differentiable variables which has the potential to be used for exploration and enhanced sampling purposes.Comment: 28 pages, 13 figure

Structural Mechanism of ω-Currents in a Mutated Kv7.2 Voltage Sensor Domain from Molecular Dynamics Simulations

Activation of voltage-gated ion channels is regulated by conformational changes of the voltage sensor domains (VSDs), four water- and ion-impermeable modules peripheral to the central, permeable pore domain. Anomalous currents, defined as ω-currents, have been recorded in response to mutations of residues on the VSD S4 helix and associated with ion fluxes through the VSDs. In humans, gene defects in the potassium channel Kv7.2 result in a broad range of epileptic disorders, from benign neonatal seizures to severe epileptic encephalopathies. Experimental evidence suggests that the R207Q mutation in S4, associated with peripheral nerve hyperexcitability, induces ω-currents at depolarized potentials, but the fine structural details are still elusive. In this work, we use atom-detailed molecular dynamics simulations and a refined model structure of the Kv7.2 VSD in the active conformation in a membrane/water environment to study the effect of R207Q and four additional mutations of proven clinical importance. Our results demonstrate that the R207Q mutant shows the most pronounced increase of hydration in the internal VSD cavity, a feature favoring the occurrence of ω-currents. Free energy and kinetics calculations of sodium permeation through the native and mutated VSD indicate as more favorable the formation of a cationic current in the latter. Overall, our simulations establish a mechanistic linkage between genetic variations and their physiological outcome, by providing a computational description that includes both thermodynamic and kinetic features of ion permeation associated with ω-currents

Thermodynamics and kinetics of ion permeation in wild-type and mutated open active conformation of the human α7 nicotinic receptor

Molecular studies of human pentameric ligand-gated ion channels expressed in neurons and at neuromuscular junctions are of utmost importance in the development of therapeutic strategies for neurological disorders. We focus here on the nicotinic acetylcholine receptor nAChR-α7, a homopentameric channel widely expressed in the human brain, with a proven role in a wide spectrum of disorders including schizophrenia and Alzheimer disease. By exploiting an all-atom structural model of the full (transmem- brane and extracellular) protein in the open, agonist-bound conformation we recently developed, we evaluate the free energy and the mean first passage time of single-ion permeation using Molecular Dynamics simulations and the milestoning method with Voronoi tessellation. The results for the wild-type channel provide the first available mapping of the potential of mean force in the full-length α7 nAChR, reveal its expected cationic nature, and are in good agreement with simulation data for other channels of the LGICs family and with experimental data on nAChRs. We then investigate the role of a specific mutation directly related to ion selectivity in LGICs, the E-1' → A-1' substitution at the cytoplasmatic selectivity filter. We find that the mutation strongly affects sodium and chloride permeation in opposite directions, leading to a complete inversion of selectivity, at variance with the limited experimental results available that classify this mutant as cationic. We thus provide structural determinants for the ob- served cationic-to-anionic inversion, revealing a key role of the protonation state of residue rings far from the mutation, in the proximity of the hydrophobic channel gate

Correction: A refined model of claudin-15 tight junction paracellular architecture by molecular dynamics simulations.

[This corrects the article DOI: 10.1371/journal.pone.0184190.]

Computational study of ion permeation through claudin‐4 paracellular channels

Claudins (Cldns) form a large family of protein homologs that are essential for the assembly of paracellular tight junctions (TJs), where they form channels or barriers with tissue‐specific selectivity for permeants. In contrast to several family members whose physiological role has been identified, the function of claudin 4 (Cldn4) remains elusive, despite experimental evidence suggesting that it can form anion‐selective TJ channels in the renal epithelium. Computational approaches have recently been employed to elucidate the molecular basis of Cldns’ function, and hence could help in clarifying the role of Cldn4. In this work, we use structural modeling and all‐atom molecular dynamics simulations to transfer two previously introduced structural models of Cldn‐based paracellular complexes to Cldn4 to reproduce a paracellular anion channel. Free energy calculations for ionic transport through the pores allow us to establish the thermodynamic properties driving the ion‐selectivity of the structures. While one model shows a cavity permeable to chloride and repulsive to cations, the other forms barrier to the passage of all the major physiological ions. Furthermore, our results confirm the charge selectivity role of the residue Lys65 in the first extracellular loop of the protein, rationalizing Cldn4 control of paracellular permeability