Effect of hydrogen bonds on polarizability of a water molecule in (H2O)(N) (N = 6, 10, 20) isomers.

Abstract: Polarizabilities of the low-lying isomers of (H2O)N (N = 6, 10, 20) clusters were computed by using Density Functional Theory. The global polarizabilities of the water isomers were found to depend mainly on the total number of water molecules rather than their cluster structures. We show that this result hides in fact a strong heterogeneity of the molecular polarizability within the different isomers. The global polarizability of a cluster was divided into a sum of molecular contributions by using the Hirshfeld partitioning scheme. We reveal that the value of the local polarizability of a molecule in the cluster is correlated with the number and type of the hydrogen bonds (HB) the…

A Hirshfeld partitioning of polarizabilities of water clusters

International audience; A new Hirshfeld partitioning of cluster polarizability into intrinsic polarizabilities and charge delocalization contributions is presented. For water clusters, density-functional theory calculations demonstrate that the total polarizability of a water molecule in a cluster depends upon the number and type of hydrogen bonds the molecule makes with its neighbors. The intrinsic contribution to the molecular polarizability is transferable between water molecules displaying the same H-bond scheme in clusters of different sizes, and geometries, while the charge delocalization contribution also depends on the cluster size. These results could be used to improve the existin…

Influence of structure on the polarizability of hydrated methane sulfonic acid clusters

Abstract: The relationship between polarizability and structure is investigated in methane sulfonic acid (MSA) and in 36 hydrated MSA clusters. The polarizabilities are calculated at B3LYP and MP2 level and further partitioned into molecular contributions using classic and iterative Hirshfeld methods. The differences in the two approaches for partitioning of polarizabilities are thoroughly analyzed. The polarizabilities of the molecules are found to be influenced in a systematic way by the hydrogen bond network in the clusters, proton transfer between MSA and water molecules, and weak interactions between water molecules and the methyl group of MSA.

Reconstructing the free-energy landscape of Met-enkephalin using dihedral principal component analysis and well-tempered metadynamics

Well-Tempered Metadynamics (WTmetaD) is an efficient method to enhance the reconstruction of the free-energy surface of proteins. WTmetaD guarantees a faster convergence in the long time limit in comparison with the standard metadynamics. It still suffers however from the same limitation, i.e. the non trivial choice of pertinent collective variables (CVs). To circumvent this problem, we couple WTmetaD with a set of CVs generated from a dihedral Principal Component Analysis (dPCA) on the Ramachadran dihedral angles describing the backbone structure of the protein. The dPCA provides a generic method to extract relevant CVs built from internal coordinates. We illustrate the robustness of this …

MgO/Ag(100): confined vibrational modes in the limit of ultrathin films

The vibrational modes of clean MgO films are investigated vs film thickness by means of high-resolution electron energy-loss spectroscopy. For thin films (20\char21{}30 monolayers) we observe, in accord with the literature, the Fuchs-Kliewer phonon at $677{\mathrm{cm}}^{\ensuremath{-}1}$ and the Wallis mode at $524{\mathrm{cm}}^{\ensuremath{-}1}.$ For ultrathin films standing wave optical phonons confined in the overlayer are present, whose frequencies depend strongly on film thickness. Comparison with theoretical calculations for MgO slabs on a perfect conductor shows that the experimental frequencies are lower than expected, indicating the presence of compressive stress. At and below one-…

Raman and Infrared Spectra of Acoustical, Functional Modes of Proteins from All-Atom and Coarse-Grained Normal Mode Analysis

The directions of the largest thermal fluctuations of the structure of a protein in its native state are the directions of its low-frequency modes (below 1 THz), named acoustical modes by analogy with the acoustical phonons of a material. The acoustical modes of a protein assist its conformational changes and are related to its biological functions. Low-frequency modes are difficult to detect experimentally. A survey of experimental data of low-frequency modes of proteins is presented. Theoretical approaches, based on normal mode analysis, are of first interest to understand the role of the acoustical modes in proteins. In this chapter, the fundamentals of normal mode analysis using all-ato…

Angstrom-Size Defect Creation and Ionic Transport through Pores in Single-Layer MoS2

Atomic-defect engineering in thin membranes provides opportunities for ionic and molecular filtration and analysis. While molecular-dynamics (MD) calculations have been used to model conductance through atomic vacancies, corresponding experiments are lacking. We create sub-nanometer vacancies in suspended single-layer molybdenum disulfide (MoS2) via Ga+ ion irradiation, producing membranes containing ∼300 to 1200 pores with average and maximum diameters of ∼0.5 and ∼1 nm, respectively. Vacancies exhibit missing Mo and S atoms, as shown by aberration-corrected scanning transmission electron microscopy (AC-STEM). The longitudinal acoustic band and defect-related photoluminescence were observe…

Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil–based chemotherapy.

Background & Aims Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil–based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T 17 intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin. We investigated whether HSP110 T 17 could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. Methods We characterized the interaction between HSP110 and HSP110DE9 using su…

Modelling of the cation motions in complex system: case of Na-mordenites

Abstract Semi-empirical inter-atomic potentials and Monte Carlo algorithms are proposed to predict the evolution of the interaction energy between sodium ions and a mordenite type aluminosilicate network as a function of Si/Al ratio. This result is favourably compared with the activation energy barriers for Na + `jumps' responsible for the polarization change, measured by thermally stimulated current (TSC) spectroscopy, for Na-mordenites characterized by Si/Al ratios ranged from 5.5 to 12. Finally, we propose a possible mechanism for the cation motions, which involves activation barriers within the same order of magnitude than those measured by TSC.

A Route toward Protein Sequencing using Solid-State Nanopores Assisted by Machine Learning

Solid-State Nanopores made of 2-D materials such as MoS2 have emerged as one of the most versatile sensors for single-biomolecule detection, which is essential for early disease diagnosis (biomarker detection). One of the most promising applications of SSN is DNA and protein sequencing, at a low cost and faster than the current standard methods. The detection principle relies on measuring the relatively small variations of ionic current as charged biomolecules immersed in an electrolyte traverse the nanopore, in response to an external voltage applied across the membrane. The passage of a biomolecule through the pore yields information about its structure and chemical properties, as demonst…

Human Inducible Hsp70: Structures, Dynamics, and Interdomain Communication from All-Atom Molecular Dynamics Simulations

The 70 kDa human heat shock protein is a major molecular chaperone involved in de novo folding of proteins in vivo and refolding of proteins under stress conditions. Hsp70 is related to several "misfolding diseases" and other major pathologies, such as cancer, and is a target for new therapies. Hsp70 is comprised of two main domains: an N-terminal nucleotide binding domain (NBD) and a C-terminal substrate protein binding domain (SBD). The chaperone function of Hsp70 is based on an allosteric mechanism. Binding of ATP in NBD decreases the affinity of the substrate for SBD, and hydrolysis of ATP is promoted by binding of polypeptide segments in the SBD. No complete structure of human Hsp70 is…

Investigation of Phosphorylation-Induced Folding of an Intrinsically Disordered Protein by Coarse-Grained Molecular Dynamics

Apart from being the most common mechanism of regulating protein function and transmitting signals throughout the cell, phosphorylation has an ability to induce disorder-to-order transition in an intrinsically disordered protein. In particular, it was shown that folding of the intrinsically disordered protein, eIF4E-binding protein isoform 2 (4E-BP2), can be induced by multisite phosphorylation. Here, the principles that govern the folding of phosphorylated 4E-BP2 (pT37pT46 4E-BP2(18–62)) are investigated by analyzing canonical and replica exchange molecular dynamics trajectories, generated with the coarse-grained united-residue force field, in terms of local and global motions and the time…

An ab initio softness metric to measure the similarity between all pairs of amino acids

Abstract The search for quantitative index of similarity between molecular moeties is important for its applications in pharmacology. Similarity is also an important concept in computational biology to measure the exchangeability of an amino acid by another in a protein sequence. In the present work, a distance between two molecules based on local and global softnesses of their fragments is defined. The method proposed is general and could be applied to any molecular library. It is first applied to compute the distance between the 190 pairs of different amino acids in their neutral states. Two amino acids belonging to the one of the biochemical class (aliphatic, sulfur-containing, acidic, ……

DFT study of polarizabilities and dipole moments of water clusters

Density functional theory (DFT) calculations with different exchange- correlation functionals, Becke's three-parameter exchange functional and the gradient- corrected functional of Lee, Yang, and Paar (B3LYP) and Becke's three-parameter functional with Perdew-Wang correlational functional (B3PW91), are performed to study the dielectric properties of small and medium-sized water clusters. For these H- bonded systems, we optimize the geometries and compute the dipole moments and polarizabilities using a supermolecule approach. The corresponding properties of the individual water molecules in the clusters are extracted from the molecular properties using the Hirshfeld expansion of the electron…

Investigation of protein folding by coarse-grained molecular dynamics with the UNRES force field.

Coarse-grained molecular dynamics simulations offer a dramatic extension of the time-scale of simulations compared to all-atom approaches. In this article, we describe the use of the physics-based united-residue (UNRES) force field, developed in our laboratory, in protein-structure simulations. We demonstrate that this force field offers about a 4000-times extension of the simulation time scale; this feature arises both from averaging out the fast-moving degrees of freedom and reduction of the cost of energy and force calculations compared to all-atom approaches with explicit solvent. With massively parallel computers, microsecond folding simulation times of proteins containing about 1000 r…

Relation between the Fukui function and the Coulomb hole

By using a coarse-grain representation of the molecular electronic density, we demonstrate that the value of the condensed Fukui function at an atomic site is directly related to the polarization charge (Coulomb hole) induced by a test electron removed (or added) from (at) the atom. The link between the formation of an electron-hole pair and the condensed Fukui function provides insights on the possible negativity of the Fukui function which is interpreted in terms of two phenomena: overscreening and over-strengthening.

New Insights into Protein (Un)Folding Dynamics.

A fundamental open problem in biophysics is how the folded structure of the main chain (MC) of a protein is determined by the physics of the interactions between the side-chains (SCs). All-atom molecular dynamics simulations of a model protein (Trp-cage) revealed that strong correlations between the motions of the SCs and the MC occur transiently at 380 K in unfolded segments of the protein, and during the simulations of the whole amino-acid sequence at 450 K. The high correlation between the SC and MC fluctuations is a fundamental property of the unfolded state and is also relevant to unstructured proteins as Intrinsically Disordered Proteins (IDPs), for which new reaction coordinates are …

Cations mobility and water adsorption in zeolites

As already pointed out [1], dielectric relaxation spectroscopy can be a convenient tool for probing ion dynamic in solids which depends on i) the structure in which ions are embedded and ii) the nature of the interaction ion/network. Consequently, the results obtained from this technique can be used as a data base for theoretical studies which goal is to calculate the ion binding energy and to simulate ionic displacements. Inversely, theoretical calculations are essential for confirming the experimental data and more particularly the method which is used for analysing the dielectric experimental response.

Decipher the mechanisms of protein conformational changes induced by nucleotide binding through free-energy landscape analysis: ATP binding to Hsp70.

ATP regulates the function of many proteins in the cell by transducing its binding and hydrolysis energies into protein conformational changes by mechanisms which are challenging to identify at the atomic scale. Based on molecular dynamics (MD) simulations, a method is proposed to analyze the structural changes induced by ATP binding to a protein by computing the effective free-energy landscape (FEL) of a subset of its coordinates along its amino-acid sequence. The method is applied to characterize the mechanism by which the binding of ATP to the nucleotide-binding domain (NBD) of Hsp70 propagates a signal to its substrate-binding domain (SBD). Unbiased MD simulations were performed for Hsp…

Softness Kernel and Nonlinear Electronic Responses

Static and Dynamic Properties of the Nonframework Cations in Na-Mordenites Zeolite

This work consists of exploring the effect of Si/Al ratio and water content on both the static and dynamic properties of the extra-framework cations in a typical zeolite system Na+-Mordenites. Atomistic simulations based on interatomic potentials and minimisation techniques have been used to determine the location of the cations as a function of the Si/Al ratio and the hydration level. Our calculations showed two different cation behaviours depending on the type of channels that they occupy, the positions of the cations in the main channels being substantially perturbed upon the sorption of water molecules whereas those of the cations located in the small side channels being only slightly s…

Effect of structural parameters on the polarizabilities of methanol clusters: a hirshfeld study

The polarizabilities of fifty methanol clusters (CH3OH)n, n = 1 to 12, were calculated at the B3LYP/6-311++G** level of theory and partitioned into molecular contributions using the Hirshfeld-I method. The resulting molecular polarizabilities were found to be determined by the polarizabilities of the two parts of the molecule, the hydrophilic hydroxyl group and the hydrophobic methyl group, each exhibiting a different dependency upon the local environment. The polarizability of the hydroxyl group was found to be dependent on the number, type, and strength of the hydrogen bonds a methanol molecule makes, whereas the polarizability of the methyl groups is mostly influenced by sterical hindran…

Density functional theory fragment descriptors to quantify the reactivity of a molecular family: Application to amino acids

By using the exact density functional theory, one demonstrates that the value of the local electronic softness of a molecular fragment is directly related to the polarization charge (Coulomb hole) induced by a test electron removed (or added) from (at) the fragment. Our finding generalizes to a chemical group a formal relation between these molecular descriptors recently obtained for an atom in a molecule using an approximate atomistic model [P. Senet and M. Yang, J. Chem. Sci. 117, 411 (2005)]. In addition, a practical ab initio computational scheme of the Coulomb hole and related local descriptors of reactivity of a molecular family having in common a similar fragment is presented. As a b…

Local vs global motions in protein folding

It is of interest to know whether local fluctuations in a polypeptide chain play any role in the mechanism by which the chain folds to the native structure of a protein. This question is addressed by analyzing folding and non-folding trajectories of a protein; as an example, the analysis is applied to the 37-residue triple β-strand WW domain from the Formin binding protein 28 (FBP28) (PDB ID: 1E0L). Molecular dynamics (MD) trajectories were generated with the coarse-grained united-residue force field, and one- and two-dimensional free-energy landscapes (FELs) along the backbone virtual-bond angle θ and backbone virtual-bond-dihedral angle γ of each residue, and principal components, respect…

Dependence of the energy of water molecules in clusters upon hydrogen bonds: a Hirshfeld study

Abstract: The energy of water clusters, containing up to 20 water molecules, are partitioned into molecular contributions using the Hirshfeld method at the DFT level. The molecular energies are analyzed with respect to the hydrogen bonding network in the clusters.

Conformational dynamics of full-length inducible human Hsp70 derived from microsecond molecular dynamics simulations in explicit solvent

Human 70 kDa heat shock protein (hHsp70) is an ATP-dependent chaperone and is currently an important target for developing new drugs in cancer therapy. Knowledge of the conformations of hHsp70 is central to understand the interactions between its nucleotide-binding domain (NBD) and substrate-binding domain (SBD) and is a prerequisite to design inhibitors. The conformations of ADP-bound (or nucleotide-free) hHsp70 and ATP-bound hHsp70 was investigated by using unbiased all-atom molecular dynamics (MD) simulations of homology models of hHsp70 in explicit solvent on a timescale of .5 and 2.7 μs, respectively. The conformational heterogeneity of hHsp70 was analyzed by computing effective free-e…

Curvature and Torsion of Protein Main Chain as Local Order Parameters of Protein Unfolding

International audience; Thermal protein unfolding resembles a global (two-state) phase transition. At the local scale, protein unfolding is, however, heterogeneous and probe dependent. Here, we consider local order parameters defined by the local curvature and torsion of the protein main chain. Because chemical shift (CS) measured by NMR spectroscopy is extremely sensitive to the local atomic environment, CS has served as a local probe of thermal unfolding of proteins by varying the position of the atomic isotope along the amino-acid sequence. The variation of the CS of each C(alpha) atom along the sequence as a function of the temperature defines a local heat-induced denaturation curve. We…