Equation of State Based Slip Spring Model for Entangled Polymer Dynamics

A mesoscopic, mixed particle- and field-based Brownian dynamics methodology for the simulation of entangled polymer melts has been developed. Polymeric beads consist of several Kuhn segments, and their motion is dictated by the Helmholtz energy of the sample, which is a sum of the entropic elasticity of chain strands between beads, slip springs, and nonbonded interactions. The entanglement effect is introduced by the slip springs, which are springs connecting either nonsuccessive beads on the same chain or beads on different polymer chains. The terminal positions of slip springs are altered during the simulation through a kinetic Monte Carlo hopping scheme, with rate-controlled creation/destruction processes for the slip springs at chain ends. The rate constants are consistent with the free energy function employed and satisfy microscopic reversibility at equilibrium. The free energy of nonbonded interactions is derived from an appropriate equation of state, and it is computed as a functional of the local density by passing an orthogonal grid through the simulation box; accounting for it is necessary for reproducing the correct compressibility of the polymeric material. Parameters invoked by the mesoscopic model are derived from experimental volumetric and viscosity data or from atomistic molecular dynamics simulations, establishing a "bottom-up" predictive framework for conducting slip spring simulations of polymeric systems of specific chemistry. The mesoscopic simulation methodology is implemented for the case of cis-1,4-polyisoprene, whose structure, dynamics, thermodynamics, and linear rheology in the melt state are quantitatively predicted and validated without a posteriori fitting the results to experimental measurements.Comment: 80 pages, 17 figure

Mesoscopic simulations of crosslinked polymer networks

Institut für Theoretische Physik, Georg-August Universität, Göttingen, Germany E-mail: [email protected] Abstract. A new methodology and the corresponding C++ code for mesoscopic simulations of elastomers are presented. The test system, crosslinked cis-1,4-polyisoprene, is simulated with a Brownian Dynamics/kinetic Monte Carlo algorithm as a dense liquid of soft, coarse-grained beads, each representing 5-10 Kuhn segments. From the thermodynamic point of view, the system is described by a Helmholtz free-energy containing contributions from entropic springs between successive beads along a chain, slip-springs representing entanglements between beads on different chains, and non-bonded interactions. The methodology is employed for the calculation of the stress relaxation function from simulations of several microseconds at equilibrium, as well as for the prediction of stress-strain curves of crosslinked polymer networks under deformation. Introduction Atomistic and mesoscopic simulations are widely employed for the study of polymer systems, since they provide insights that are complementary to the information derived from experiments. Although the full-atom or united-atom representations provide an accurate description of polymers, their long relaxation time constitutes a severe obstacle to such approaches, and thus the development of mesoscopic (or coarse-grained) models is needed to cover longer time and length scales. One of the main characteristics of polymer melts and polymer networks is the entanglement effect, arising due to the uncrossability of polymer chains, which gives rise to complicated topological constraints [1]-[4]. The tube model, which considers a single chain in a mean field, is one of the most significant models for the description of entangled polymer

Comparative study of the AT1 receptor prodrug antagonist candesartan cilexetil with other sartans on the interactions with membrane bilayers

AbstractDrug–membrane interactions of the candesartan cilexetil (TCV-116) have been studied on molecular basis by applying various complementary biophysical techniques namely differential scanning calorimetry (DSC), Raman spectroscopy, small and wide angle X-ray scattering (SAXS and WAXS), solution 1H and 13C nuclear magnetic resonance (NMR) and solid state 13C and 31P (NMR) spectroscopies. In addition, 31P cross polarization (CP) NMR broadline fitting methodology in combination with ab initio computations has been applied. Finally molecular dynamics (MD) was applied to find the low energy conformation and position of candesartan cilexetil in the bilayers. Thus, the experimental results complemented with in silico MD results provided information on the localization, orientation, and dynamic properties of TCV-116 in the lipidic environment. The effects of this prodrug have been compared with other AT1 receptor antagonists hitherto studied. The prodrug TCV-116 as other sartans has been found to be accommodated in the polar/apolar interface of the bilayer. In particular, it anchors in the mesophase region of the lipid bilayers with the tetrazole group oriented toward the polar headgroup spanning from water interface toward the mesophase and upper segment of the hydrophobic region. In spite of their localization identity, their thermal and dynamic effects are distinct pointing out that each sartan has its own fingerprint of action in the membrane bilayer, which is determined by the parameters derived from the above mentioned biophysical techniques

Exploring the interactions of irbesartan and irbesartan–2-hydroxypropyl-β-cyclodextrin complex with model membranes

The interactions of irbesartan (IRB) and irbesartan–2-hydroxypropyl-β-cyclodextrin (HP-β-CD) complex with Dipalmitoyl Phosphatidylcholine (DPPC) bilayers have been explored utilizing an array of biophysical techniques ranging from Differential Scanning Calorimetry (DSC), Small angle X-ray Scattering (SAXS), ESI Mass-Spectrometry (ESI-MS) and solid state Nuclear Magnetic Resonance (ssNMR). Molecular Dynamics (MD) calculations have been also conducted to complement the experimental results. Irbesartan was found to be embedded in the lipid membrane core and to affect the phase transition properties of the DPPC bilayers. SAXS studies revealed that irbesartan alone does not display perfect solvation since some coexisting irbesartan crystallites are present. In its complexed form IRB gets fully solvated in the membranes showing that encapsulation of IRB in HP-β-CD may have beneficial effects in the ADME properties of this drug. MD experiments revealed the topological and orientational integration of irbesartan into the phospholipid bilayer being placed at about 1 nm from the membrane centre

Rational design, efficient syntheses and biological evaluation of N,N′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

A series of symmetrically bis-substituted imidazole analogs bearing at the N-1 and N-3 two biphenyl moieties ortho substituted either with tetrazole or carboxylate functional groups was designed based on docking studies and utilizing for the first time an extra hydrophobic binding cleft of AT1 receptor. The synthesized analogs were evaluated for their in vitro antagonistic activities (pA2 values) and binding affinities (–logIC50 values) to the Angiotensin II AT1 receptor. Among them, the potassium (–logIC50 = 9.04) and the sodium (–logIC50 = 8.54) salts of 4-butyl-N,N′-bis{[2′-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (12a and 12b, respectively) as well as its free acid 11 (–logIC50 = 9.46) and the 4-butyl-2-hydroxymethyl-N,N′-bis{[2′-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (14) (–logIC50 = 8.37, pA2 = 8.58) showed high binding affinity to the AT1 receptor and high antagonistic activity (potency). The potency was similar or even superior to that of Losartan (–logIC50 = 8.25, pA2 = 8.25). On the contrary, 2-butyl-N,N′-bis{[2′-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (27) (–logIC50 = 5.77) and 2-butyl-4-chloro-5-hydroxymethyl-N,N′-bis{[2′-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (30) (–logIC50 = 6.38) displayed very low binding affinity indicating that the orientation of the n-butyl group is of primary importance. Docking studies of the representative highly active 12b clearly showed that this molecule has an extra hydrophobic binding feature compared to prototype drug Losartan and it fits to the extra hydrophobic cavity. These results may contribute to the discovery and development of a new class of biologically active molecules through bis-alkylation of the imidazole ring by a convenient and cost effective synthetic strategy

Atomistic and mesoscopic simulations of liquid crystals and lipid membranes

Atomistic and mesoscopic models of liquid-crystals and lipid membranes are presented in this PhD thesis. These models can be regarded as an important milestone for the study of anchoring at interfaces laden with water and lipids in contact with a liquid-crystalline phase. The arrangement of molecules at the aforementioned interfaces can be exploited for the development of biosensors. Initially, an atomistic model of the water-DPPC system is studied in the phase at the temperature of 325K. The predictive ability of this model is discussed in terms of structural properties, such as tilt angles, lamellar repeat distance, order parameter of alkyl tails, and diffusion constants; all these magnitudes are compared with the corresponding experimental predictions. In addition, the NERD force field was tested for the description of DPPC alkyl tails. An important disadvantage of atomistic models for complex systems is that the time and length scales they can address are very limited. Therefore, it is extremely difficult to make use of atomistic models for the study of anchoring effects at interfaces with liquid crystals. To this end, there is a pressing need for the development of reliable mesoscopic models for the system in question. As far as the system water-DPPC at mesoscopic level is concerned, we use the model developed by Marrink et al. This is a versatile model developed for the simulation of a variety of systems (lipids, surfactants, etc). To check the consistency between the different levels of description, the structural properties obtained from the mesoscopic model were compared with those from the atomistic model. The consistency between these models is satisfactory enough, and therefore permits changing the level of description for the water-DPPC system. This comparison was necessary because the mesoscopic model was not derived from the atomistic model. The need of a mesoscopic model for 5CB molecules is pressing as well. In this case, we chose to coarse-grain a recently developed reliable atomistic model by applying the Iterative Boltzmann Inversion (IBI) method, which is quite popular for polymer systems. A five-bead representation of 5CB molecules was chosen at the mesoscopic level. Two versions of the aforementioned mesoscopic model were developed; the first is charge-free, while the second incorporates two virtual atoms with partial charges, so as to reproduce the dipole moment of the cyano group. The coarse-graining took place at 320K, where 5CB molecules are found in the isotropic phase - all molecules move randomly in space without a preferential orientation. Each iteration of the IBI method entails a Molecular Dynamics simulation of 5CB at the mesoscopic level. The resulting coarse-grained force-field reproduces fourteen atomistic structural properties at the mesoscopic level. It has to be pointed out that the standard IBI method cannot be applied for the 5CB system, since it results in divergence from the first iterations. For this reason, we modified the IBI method in order to achieve convergence for the system under study. The results are excellent, since we reproduce all chosen structural properties at the coarse-grained level. As mentioned in the previous paragraph, the development of the mesoscopic force-fields took place at 320K, where the molecules do not exhibit liquid-crystalline behavior. Both mesoscopic models were tested by means of Molecular Dynamics simulations at lower temperatures, in order to check their ability to form liquid-crystalline phases. During this testing process we concluded that the model with partial charges cannot form real liquid-crystalline phases and is less satisfactory, because it suffers from a certain degree of doublecounting of electrostatic interactions. This means that the IBI method, when applied to polar molecules, can capture electrostatic interactions into the potentials of mean force. The charge-free model predicts a smectic phase instead of the nematic one found experimentally; in addition, the transition temperature from the isotropic to the ordered phase is underestimated. To correct this, a systematic modification was undertaken for the charge-free model. Through this modification we developed a model that gives a transition point very close to the experimental value and predicts a first order transition from the thermodynamic point of view. Also, the densities in the isotropic and liquid-crystalline phase are satisfactory enough. Again, however, the predicted liquid-crystalline phase is smectic. This structure, which arises also with some atomistic models, seems to result from the coarse-graining technique employed. This modified mesoscopic model can be extended to other members of the CB family (e.g 8CB), which exhibit a smectic phase in their liquid-crystalline region.Στη παρούσα διδακτορική διατριβή παρουσιάζονται ατομιστικά και μεσοσκοπικά μοντέλα υγρών κρυστάλλων και λιπιδικών μεμβρανών, τα οποία μπορούν να αποτελέσουν το πρώτο σημαντικό βήμα για τη μελέτη της αγκύρωσης σε διεπιφάνειες με νερό και λιπίδια, ευρισκόμενα σε επαφή με μια υγροκρυσταλλική φάση. Οι μεταβολές που συμβαίνουν στις προαναφερθείσες διεπιφάνειες μπορούν να αξιοποιηθούν για τον σχεδιασμό βιοαισθητήρων. Αρχικά μελετάται σε ατομιστικό επίπεδο το σύστημα νερό-DPPC ευρισκόμενο στη φάση (325K). Η καταλληλότητα αυτού του μοντέλου συζητείται σε όρους δομικών ιδιότητων (λ.χ γωνίες κλίσης, επαναλαμβανόμενη απόσταση φυλλιδίου, παράμετρος τάξης για τις αλκυλικές αλυσίδες, κλπ) και συντελεστών διάχυσης· επιπλέον τα μεγέθη αυτά συγκρίνονται με τις αντίστοιχες πειραματικές προβλέψεις. Επίσης, μελετάται η ικανότητα του πεδίου δυνάμεων NERD να περιγράψει τις αλκυλικές αλυσίδες των μορίων DPPC. Σημαντικό μειονέκτημα των ατομιστικών μοντέλων για πολύπλοκα συστήματα, όπως είναι το σύστημα νερό-DPPC, αποτελεί η περιορισμένη χρονική και χωρική κλίμακα τις οποίες καλύπτουν. Φαινόμενα αγκύρωσης σε διεπιφάνειες με υγρούς κρυστάλλους είναι πολύ δύσκολο να μελετηθούν με ατομιστικά μοντέλα, λόγω των πολύ μικρών χρόνων που καλύπτουν. Επομένως, κρίνεται αναγκαία η χρήση μεσοσκοπικών μοντέλων τόσο για το σύστημα νερό-DPPC όσο και για την υγροκρυσταλλική φάση που στη συγκεκριμένη περίπτωση είναι τα μόρια 5CB. Σαν μεσοσκοπικό μοντέλο της λιπιδικής διπλοστιβάδας χρησιμοποιείται εκείνο που έχει αναπτυχθεί από τον Marrink και τους συνεργάτες του, το οποίο είναι ευρέως αποδεκτό από την επιστημονική κοινότητα. Ένα από τα σημαντικότερα πλεονεκτήματά του είναι η ικανότητα περιγραφής πολλών συστημάτων, αφού βασίζεται στη χρήση κατάλληλων ομάδων που μπορούν να δομήσουν αρκετά μόρια (άλλα λιπίδια πέρα από το DPPC, κάποια τασιενεργά μόρια κλπ). Για να υπάρχει συνέπεια μεταξύ των δύο διαφορετικών επιπέδων προσομοίωσης συγκρίθηκαν οι δομικές ιδιότητες του συστήματος νερό-DPPC σε μεσοσκοπικό επίπεδο με εκείνες που υπολογίζονται από το χρησιμοποιούμενο ατομιστικό μοντέλο. Η συνέπεια μεταξύ αυτών των μοντέλων κρίνεται ικανοποιητική και επομένως μπορούμε να απομακρυνθούμε από την ατομιστική κλίμακα. Έχοντας ένα αξιόπιστο μεσοσκοπικό μοντέλο για την υπό μελέτη λιπιδική μεμβράνη, θα πρέπει να αναπτυχθεί επίσης και ένα μεσοσκοπικό μοντέλο για το σύστημα των μορίων 5CB. Στη συγκεκριμένη περίπτωση επιλέξαμε να αρχίσουμε από ένα καλά ελεγμένο ατομιστικό μοντέλο. Η αναπαράσταση ενός μορίου 5CB σε μεσοσκοπικό επίπεδο επιλέχθηκε να γίνει με πέντε αδροποιημένες μονάδες (χάντρες). Η συγκεκριμένη αναπαράσταση παρουσιάζεται σε δυο εκδοχές: η μια στερείται ηλεκτροστατικών αλληλεπιδράσεων, ενώ η άλλη περιέχει εικονικά άτομα (virtual atoms) που φέρουν μερικά φορτία, ώστε να αναπαράγεται η διπολική ροπή του ατομιστικού κυανίου σε μεσοσκοπικό επίπεδο. Η διαδικασία ανάπτυξης των δυναμικών, που βασίζεται στη μέθοδο IBI (Iterative Boltzmann Inversion), έλαβε χώρα στους 320Κ, όπου τα μόρια βρίσκονται στην ισότροπη φάση. Κάθε επανάληψη της μεθόδου IBI απαιτεί μια προσομοίωση αδροποιημένης Μοριακής Δυναμικής των μορίων 5CB. Τα δυναμικά που προέκυψαν αναπαράγουν πλήρως σε μεσοσκοπικό επίπεδο δεκατέσσερις δομικές ιδιότητες που υπολογίστηκαν από το ατομιστικό μοντέλο. Στο σημείο αυτό θα πρέπει να τονιστεί ότι η μέθοδος IBI, που χρησιμοποιείται ευρέως για πολυμερικά συστήματα, δεν εφαρμόστηκε ως έχει για τα μόρια 5CB λόγω της ταχείας απόκλισης που εμφάνισε από τις πρώτες κιόλας επαναλήψεις. Για αυτό το λόγο τροποποιήσαμε την μέθοδο IBI, ώστε να πετύχουμε σύγκλιση για το υπό μελέτη σύστημα. Η εφαρμογή της τροποποιημένης μεθόδου κρίνεται πολύ ικανοποιητική, αφού πετύχαμε σύγκλιση δεκατεσσάρων συναρτήσεων σε μεσοσκοπικό επίπεδο για σχετικά μικρό αριθμό επαναλήψεων

Equation of state based slip spring model for entangled polymer dynamics

A mesoscopic, mixed particle- and field-based Brownian dynamics methodology for the simulation of entangled polymer melts has been developed. Polymeric beads consist of several Kuhn segments, and their motion is dictated by the Helmholtz energy of the sample, which is a sum of the entropic elasticity of chain strands between beads, slip springs, and nonbonded interactions. Following earlier works in the field [Phys. Rev. Lett. 2012, 109, 148302], the entanglement effect is introduced by the slip springs, which are springs connecting either nonsuccessive beads on the same chain or beads on different polymer chains. The terminal positions of slip springs are altered during the simulation through a kinetic Monte Carlo hopping scheme, with rate-controlled creation/destruction processes for the slip springs at chain ends. The rate constants are consistent with the free energy function employed and satisfy microscopic reversibility at equilibrium. The free energy of nonbonded interactions is derived from an appropriate equation of state, and it is computed as a functional of the local density by passing an orthogonal grid through the simulation box; accounting for it is necessary for reproducing the correct compressibility of the polymeric material. Parameters invoked by the mesoscopic model are derived from experimental volumetric and viscosity data or from atomistic molecular dynamics simulations, establishing a “bottom-up” predictive framework for conducting slip spring simulations of polymeric systems of specific chemistry. Initial configurations for the mesoscopic simulations are obtained by further coarse-graining of well-equilibrated structures represented at a greater level of detail. The mesoscopic simulation methodology is implemented for the case of cis-1,4-polyisoprene, whose structure, dynamics, thermodynamics, and linear rheology in the melt state are quantitatively predicted and validated without a posteriori fitting the results to experimental measurements

Molecular simulations of fluoxetine in hydrated lipid bilayers, as well as in aqueous solutions containing β-cyclodextrin

Fluoxetine, which is a well-known antidepressant drug, is studied in hydrated cholesterol-free and cholesterol-containing lipid bilayers through unbiased and biased atomistic molecular dynamics simulations. The latter are conducted for the calculation of the potential of mean force (PMF) of fluoxetine along an axis perpendicular to the two leaflets of the bilayer. The PMF indicates that the drug prefers to reside inside the lipid phase and allows us to calculate important thermodynamic properties, such as the Gibbs energy difference of partitioning from the water to the lipid phase and the Gibbs energy barrier for hopping events between the two leaflets of the bilayer. The results from the biased simulations are in accord with the mass density profiles calculated from the unbiased simulations. Moreover, we estimate the effect of fluoxetine mole fraction on the order parameters of the lipid alkyl chains and on the area per lipid. It is also found that fluoxetine forms a hydrogen bond network with lipids and water molecules penetrating into the lipid phase. In addition, fluoxoetine is studied in detail in aqueous solutions containing β-cyclodextrin. It is observed from unbiased molecular dynamics simulations that the two aforementioned molecules form a noncovalent complex spontaneously and the calculated binding free energy is in agreement with the literature. © 2022 Elsevier Inc

Systematic Coarse Graining of 4-Cyano-4′-pentylbiphenyl

International audienceA coarse-grained model is derived for a liquid-crystal-forming molecule, 4-cyano-4′-pentylbiphenyl (5CB), from a detailed atomistic model using the iterative Boltzmann inversion (IBI) method in the isotropic phase at 315 K and 1 bar. The coarse-grained model consists of five “superatoms” (one for the cyano group, two for the aromatic rings in the biphenyl moiety, and two for the alkyl tail), which are categorized as three types. A modification of IBI, wherein only one of the effective intermolecular potentials (the one corresponding to the superatom pair whose intermolecular correlation function exhibits the highest deviation from the atomistic one) is updated at each iteration, proves to be necessary to achieve convergence. The coarse-grained model, which enables a savings of a factor of 35 in computational cost relative to atomistic simulation, is used to explore ordering into liquid-crystalline phases at lower temperatures. It is found to yield a first-order ordering transition at 288 K with small hysteresis and negligible system size effects. A detailed investigation in terms of various structural and dynamical measurements indicates that the ordered phase is of the smectic type rather than nematic, as observed experimentally. The ordering temperature can be brought close to the experimental value of 308.5 K through the simple rescaling of the intermolecular effective interaction potentials employed in the coarse-grained model. A nematic ordered phase can be obtained from the coarse-grained model by scaling up the head-head and tail-tail effective interaction potentials obtained by IBI