Characterization of 3D Voronoi Tessellation Nearest Neighbor Lipid Shells Provides Atomistic Lipid Disruption Profile of Protein Containing Lipid Membranes

Quantifying protein-induced lipid disruptions at the atomistic level is a challenging problem in membrane biophysics. Here we propose a novel 3D Voronoi tessellation nearest-atom-neighbor shell method to classify and characterize lipid domains into discrete concentric lipid shells surrounding membrane proteins in structurally heterogeneous lipid membranes. This method needs only the coordinates of the system and is independent of force fields and simulation conditions. As a proof-of-principle, we use this multiple lipid shell method to analyze the lipid disruption profiles of three simulated membrane systems: phosphatidylcholine, phosphatidylcholine/cholesterol, and beta-amyloid/phosphatidylcholine/cholesterol. We observed different atomic volume disruption mechanisms due to cholesterol and beta-amyloid. Additionally, several lipid fractional groups and lipid-interfacial water did not converge to their control values with increasing distance or shell order from the protein. This volume divergent behavior was confirmed by bilayer thickness and chain orientational order calculations. Our method can also be used to analyze high-resolution structural experimental data

Protein-water interactions studied by molecular dynamics simulations

Most proteins have evolved to function optimally in aqueous environments, and the interactions between protein and water therefore play a fundamental role in the stability, dynamics, and function of proteins. Although we understand many details of water, we understand much less about the protein-water interface. In this thesis we use molecular dynamics (MD) simulations to cast light on many structural and dynamical properties of protein hydration for which a detailed picture is lacking.We show that the 1 ms MD simulation of the bovine pancreatic trypsin inhibitor (BPTI) by Shaw \textsl{et al.} (Science 2010, 330, 341) reproduces the mean survival times from magnetic relaxation dispersion (MRD) experiments by computing the relevant survival correlation function that is probed by these experiments. The simulation validates several assumptions in the model used to interpret MRD data, and reveals a possible mechanism for the water-exchange; water molecules gain access to the internal sites by a transient aqueduct mechanism, migrating as single-file water chains through transient tunnels or pores. The same simulation was also used to reveal a possible mechanism for hydrogen exchange of backbone amides, involving short-lived locally distorted conformations of the protein whereby the amide is presolvated by two water molecules before the catalyst can approach the amide through a water wire.We perform MD simulations of several small globular proteins in dilute aqueous solution to spatially resolve protein hydration. Defining mono-molecular thick hydration shells as a metric from the protein surface, we compute structural and dynamical properties of water in these shells and show that the protein-induced water perturbation is short ranged, essentially only affecting water molecules in the first hydration shell, thus validating the model used to interpret MRD data. Compared to the bulk, the first shell is 6 \% more dense and 25-30 \% less compressible. The shell-averaged rotation of water molecules in the first hydration shell is retarded by a factor 4-5 compared to bulk, and the contributions to this retardation can be resolved based on a universal confinement index. The dynamical heterogeneity in the first shell is a result of water molecules rotating by different mechanisms on a spectrum between two extremes: a collective bulk-like mechanism and a protein-coupled mechanism where water molecules in confined sites are orientationally restricted and require an exchange event

Shelling the Voronoi interface of protein-protein complexes predicts residue activity and conservation

The accurate description of protein-protein interfaces remains a challenging task. Traditional criteria, based on atomic contacts or changes in solvent accessibility, tend to over or underpredict the interface itself and cannot discriminate active from less relevant parts. A recent simulation study by Mihalek and co-authors (2007, JMB 369, 584-95) concluded that active residues tend to be `dry', that is, insulated from water fluctuations. We show that patterns of `dry' residues can, to a large extent, be predicted by a fast, parameter-free and purely geometric analysis of protein interfaces. We introduce the shelling order of Voronoi facets as a straightforward quantitative measure of an atom's depth inside an interface. We analyze the correlation between Voronoi shelling order, dryness, and conservation on a set of 54 protein-protein complexes. Residues with high shelling order tend to be dry; evolutionary conservation also correlates with dryness and shelling order but, perhaps not surprisingly, is a much less accurate predictor of either property. Voronoi shelling order thus seems a meaningful and efficient descriptor of protein interfaces. Moreover, the strong correlation with dryness suggests that water dynamics within protein interfaces may, in first approximation, be described by simple diffusion models

Nanoscale shear cohesion between cement hydrates: The role of water diffusivity under structural and electrostatic confinement

\ua9 2022 The Authors. The calcium silicate hydrate (C-S-H) controls most of the final properties of the cement paste, including its mechanical performance. It is agreed that the nanometer-sized building blocks that compose the C-S-H are the origin of the mechanical properties. In this work, we employ atomistic simulations to investigate the relaxation process of C-S-H nanoparticles subjected to shear stress. In particular, we study the stress relaxation by rearrangement of these nanoparticles via sliding adjacent C-S-H layers separated by a variable interfacial distance. The simulations show that the shear strength has its maximum at the bulk interlayer space, called perfect contact interface, and decreases sharply to low values for very short interfacial distances, coinciding with the transition from 2 to 3 water layers and beginning of the water flow. The evolution of the shear strength as a function of the temperature and ionic confinement confirms that the water diffusion controls the shear strength

Nanoscale shear cohesion between cement hydrates: The role of water diffusivity under structural and electrostatic confinement

[EN] The calcium silicate hydrate (C-S-H) controls most of the final properties of the cement paste, including its mechanical performance. It is agreed that the nanometer-sized building blocks that compose the C-S-H are the origin of the mechanical properties. In this work, we employ atomistic simulations to investigate the relaxation process of C-S-H nanoparticles subjected to shear stress. In particular, we study the stress relaxation by rearrangement of these nanoparticles via sliding adjacent C-S-H layers separated by a variable interfacial distance. The simulations show that the shear strength has its maximum at the bulk interlayer space, called perfect contact interface, and decreases sharply to low values for very short interfacial distances, coinciding with the transition from 2 to 3 water layers and beginning of the water flow. The evolution of the shear strength as a function of the temperature and ionic confinement confirms that the water diffusion controls the shear strength.We gratefully acknowledge the financial support by "Departamento de Educacion, Politica Linguistica y Cultura del Gobierno Vasco" (IT912-16, IT1639-22). E.D.-R. acknowledges the postdoctoral fellowship from "Programa Posdoctoral de Perfeccionamiento de Personal Investigador Doctor" of the Basque Government. The authors thank for technical and human support provided by i2basque and SGIker (UPV/EHU/ERDF, EU), for the allocation of computational resources provided by the Scientific Computing Service

Structural decomposition and structural relaxation of solvation shells of hydrated molecular ionic liquids and protein solutions

Die vorliegende Arbeit liefert neue methodische Beitraege zur Untersuchung der Struktur und Dynamik von Biomolekuelen in Loesung mittels Voronoi-Analyse von Computersimulationen. Dabei werden sowohl kollektive wie auch Einteilchen-Eigenschaften der Solvathuellen und des Bulk-Mediums betrachtet. Als Modellproteine dienen Ubiquitin (PDB-code: 1UBQ), Calbindin (1CLB) und eine Phospholipase (2PLD) deren Solvatation in Wasser einen wesentlichen Bestandteil dieser Arbeit darstellt. Darueber hinaus werden Vorstudien zu Molekularen Ionischen Fluessigkeiten (MIL) angestellt die in den letzten Jahren unter anderem als umweltvertraegliche polare Loesungsmittel in den Vordergrund getreten sind. Trifluoroazetat-, Tetrafluoroborat- und Trifluoromethylsulfonat- Salze von alkyliertem Imidazolium werden einerseits in Reinform, andererseits in Mischung mit Wasser untersucht. Neu an dieser Arbeit ist zunaechst die Atom-aufgeloeste Tesselierung, die fuer Systeme mit 30000 Atomen mit periodischen Randbedingungen ueber hundertausende Zeitschritte sehr rechenintensiv, und daher nur durch die effiziente Implementierung geeigneter Algorithmen zu bewerkstelligen ist. Auf dieser Grundlage werden weitestgehend parameterfreie Ansaetze zur lokalen und globalen Strukturanalyse entwickelt die einerseits mit konventionellen Methoden wie etwa Radialen Verteilungsfunktionen und Orientierungskorrelationsfunktionen verglichen werden, andererseits zusaetzliche Moeglichkeiten der Interpretation bieten. Position und Orientierung von benachbarten Molekuelen kann direkt anhand von graphentheoretischen Interaktionen beschrieben und interpretiert werden. Ein Markov-Modell fuer die Dynamik innerhalb und zwischen einzelnen Solvathuellen wird entwickelt und auf MIL Systeme angewendet.The present work provides new methodical contributions to investigation of structural and dynamic behaviour of solvated biomolecules using Voronoi analysis of computer simulations. Thereby, collective as well as single particle properties of solvation shells and the bulk medium are considered. The three proteins ubiquitin (PDB-code: 1UBQ), calbindin (1CLB) and phospholipase (2PLD) serve as model systems. The study of their solvation in water is an integral part of this work. Moreover, preliminary studies of Molecular Ionic Liquids (MIL) are being made, that have come to the fore in recent years as environmentally compliant polar solvents. Alkylated imidazolium salts of Trifluoroacetate, Tetrafluoroborate and Trifluoromethylsulfonate are analysed in the pure form as well as mixed with water. For one thing, new in this work is the atom-resolved tesselation, that is computationally demanding for systems with about 30000 atoms and periodic boundary conditions over 100-thousands of time steps and hence is to be managed only by the efficient implementation of suitable algorithms. Widely parameter free approaches to local and global structure analysis are developed on this basis and compared to conventional methods like radial distribution functions and orientation correlation functions. Furthermore, they provide additional possibilities for interpretation. Position and orientation of neighbouring molecules can be described and interpreted directly by graph theoretical interactions. A Markov model for dynamics within and between solvation shells is being developed and applied to MIL systems

Random lattice particle modeling of fracture processes in cementitious materials

The capability of representing fracture processes in non-homogeneous media is of great interest among the scientific community for at least two reasons: the first one stems from the fact that the use of composite materials is ubiquitous within structural applications, since the advantages of the constituents can be exploited to improve material performance; the second consists of the need to assess the non-linear post-peak behavior of such structures to properly determine margins of safety with respect to strong excitations (e.g. earthquakes, blast or impact loadings). Different kinds of theories and methodologies have been developed in the last century in order to model such phenomena, starting from linear elastic equivalent methods, then moving to plastic theories and fracture mechanics. Among the different modeling techniques available, in recent years lattice models have established themselves as a powerful tool for simulating failure modes and crack paths in heterogeneous materials. The basic idea dates back to the pioneeristic work of Hrennikoff: a continuum medium can be modeled through the interaction of unidimensional elements (e.g. springs or beams) spatially arranged in different ways. The set of nodes that interconnect the elements can be regularly or irregularly placed inside the domain, leading to regular or random lattices. It has been shown that lattices with regular geometry can strongly bias the direction of cracking, leading to incorrect results. A variety of lattice models have been developed. Such models have seen a wide field of applications, ranging from aerodynamics (using Lattice-Boltzman models) to heat transfer, crystallography and many others. Every material used in civil and infrastructure engineering is constituted of different phases. This is due to the fact that the different features of different elements are usually coupled in order to obtain greater advantages with respect to the original constituents. Even structural steel, which is usually thought of as a homogeneous continuum-type medium, includes carbon particles that can be seen as inhomogeneities at the microscopic level. The mechanical behavior of concrete, which is the main object of the present work, is strongly affected not only by the presence of inclusions (i.e. the aggregates pieces) but also by their arrangement. For this reason, the explicit, statistical representation of their presence is of great interest in the simulations of concrete behavior. Lattice models can directly account for the presence of different phases, and so are advantageous from this perspective. The definition of such models, their implementation in a computer program, together with validation on laboratory tests will be presented. The present work will briefly review the state of the art and the basic principles of these models, starting from the geometrical and computing tools needed to build the simulations. The implementation of this technique in the Matlab environment will be presented, highlighting the theoretical background. The numerical results will be validated based on two complementary experimental campaigns,which focused on the meso- and macro-scales of concrete. Whereas the aim of this work is the representation of the quasi-brittle fracture processes in cementitious materials such as concrete, the discussed approach is general, and therefore valid for the representation of damage and crack growth in a variety of different materials

On Bilayer Deformation Energetics With and Without Gramicidin A Channel

Lipid membranes are not simply passive barriers. Embedded proteins are coupled to the membrane and can deform the surrounding bilayer, which incurs an energetic penalty. To minimize these penalties, proteins are known to tilt, aggregate, and experience major conformation changes. The degree to which the protein is influenced by the bilayer is dependent on the bilayer material properties and protein-bilayer coupling strength, for example. In this dissertation, the effects of bilayer material properties and protein-bilayer coupling are detailed using gramicidin A channel. This simple channel experiences one major conformational change, its transmembrane dimerization, which produces a bilayer deformation if the bilayer and dimer do not have the same hydrophobic lengths. Herein, molecular dynamics simulations are used to describe bilayer material properties, channel-bilayer coupling, and general lipid energetics with and without gramicidin A

Exploring complex cellular membranes containing lipids, cholesterols, proteins, and gangliosides using molecular simulations

Domains of different thermodynamic phases manifest in the cell membrane as a consequence of the complex interactions between lipids and proteins. One of the outstanding challenges in membrane biophysics is to understand the role played by the structural and dynamical heterogeneity of membranes in supporting cellular function. In particular, there remain fundamental open questions related to the role of proteins in lipid domain formation, the effect of protein co-localization with lipid domains, and the nanoscopic structure of lipid domains. My dissertation research systematically investigated cellular membrane environments using all-atom and coarse-grained molecular simulations. Systems of incremental complexity, binary and ternary lipid model membranes, laterally heterogeneous membranes with proteins, and membranes with gangliosides were studied. With the aid of statistical mechanics and molecular simulation algorithms, critical insights were gained into cholesterol aggregation in model membranes. Cholesterol was found to populate a dimer ensemble with distinct sub-states in contrast to the idealistic view of face-flush cholesterol dimers. Further investigations characterized the inter- and intra-leaflet interactions of cholesterols, providing insights into possible trimer and tetramer formation. To probe the dynamic interplay of lipids and proteins in lipid raft-mimicking environments, we accurately modeled laterally heterogeneous membranes and explored the colocalization of transmembrane proteins. The proteins were observed to preferably co-localize at the domain boundaries, reducing the excess free energy of forming an interface. This observation has implications in transmembrane proteins known to be involved in the biogenesis of amyloid beta protein and believed to have activity dependent on localization in raft domains. Venturing beyond ternary lipid mixtures, membranes formed from quaternary lipid mixtures that approximate the surface of an artificial virus nanoparticle were examined. The effects of cations in mediating the interactions of negatively charged lipids were established through collaborative of experimental and simulation studies. Finally, development of force field parameters for sulfated poly-amido-saccharides and also validating existing cholesterol parameters across all available force fields were also undertaken as major methodological pursuits. Taken together these studies demonstrate the power of computer simulation, well-validated by experiment, to elucidate the structural and functional nature of complex biomolecular systems