Influence of Tacticity on Hydrophobicity of Poly(N-isopropylacrylamide

Article pubs.acs.org/JPCB

Influence of Tacticity on Hydrophobicity of Poly(N‑isopropylacrylamide): A Single Chain Molecular Dynamics Simulation Study Ester Chiessi* and Gaio Paradossi Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Via della Ricerca Scientifica I, 00133 Rome, Italy W Web-Enhanced Feature * S Supporting Information *

ABSTRACT: Several pieces of experimental evidence show that the water affinity of poly(N-isopropylacrylamide), PNIPAM, decreases with the increase of the degree of isotacticity. To give a rationale to such effect we carried out atomistic molecular dynamics simulations of PNIPAM 30-mers with content of meso dyads, m, of 45% and 59%, assuming a Bernoullian dyad distribution. The single chain behavior of these stereoisomers in water was modeled at 283 and 323 K, i.e., below and above the lower critical solution temperature, LCST. Simulation results show that the dyad composition has influence on size and conformation of the oligomer below the LCST, the isotactic-rich stereoisomer preferring conformations with lower radius of gyration. With reference to the cooperative hydration model of PNIPAM, we analyzed the organization and the dynamics of water in the surroundings of the polymer. Below the LCST the number of hydrogen bonds per water molecule in the first hydration shell and the water surface concentration around PNIPAM are affected by the meso/racemo dyad ratio, showing the higher hydrophobicity of the isotactic-rich system. Above the LCST the subtle effects leading to the modulation of conformation and hydration by means of tacticity are overtaken, and the chain collapse is observed for both systems up to a similar globular state. The comparison of simulation findings of the m 45% stereoisomer with available experimental results of atactic PNIPAM highlights additional molecular details of this macromolecule in aqueous environment. The characteristic time for motion of water molecules in the PNIPAM first hydration shell at 283 K is about 34 ps, in agreement with the experimental value.

1. INTRODUCTION Poly(N-isopropylacrylamide), PNIPAM, is one of the most known thermoresponsive polymers. Aqueous solutions of this synthetic macromolecule display a lower critical solution temperature, LCST, of about 305 K for atactic PNIPAM at a high degree of polymerization. Networked systems based on PNIPAM in aqueous environment, including hydrogels, microgels, and nanogels, maintain the temperature-dependent solubility behavior of the linear homopolymer and show a volume phase transition from a swollen to a shrunk state by increasing temperature. This transition, occurring at a volume phase transition temperature, VPTT, similar to the LCST value of PNIPAM, enables several applications of these systems as smart stimuli responsive devices.1 One of the issues currently being addressed in the design of PNIPAM based soft matter systems is the tuning of the VPTT, by lowering or increasing its value depending on the specific application. In principle, this result can be achieved by exploiting the experimentally observed dependence of the LCST of PNIPAM aqueous solutions from four main factors: degree of polymerization (DP), polydispersity, concentration,2−4 and stereochemistry of the macromolecule. However, the role of the former three parameters, which in the chemically cross-linked polymer matrix find correspondence in chain length between adjacent junctions (Mc), polydispersity of Mc, and hydration degree, respectively, is reduced because of topological constraints. © 2016 American Chemical Society

Therefore, the PNIPAM stereochemistry represents a major factor for tuning the VPTT without introducing heteroresidues in the polymer scaffold.5 The synthesis of stereocontrolled linear homopolymers and gels of PNIPAM became feasible in the past decade.6−8 As a result, it was found that PNIPAM stereoregularity significantly affects the phase boundary and LCST of its aqueous solutions.9−12 The LCST of PNIPAM’s with a high meso dyad content (so-called “isotactic-rich PNIPAM”) in water is lower than that of an atactic PNIPAM.9 For PNIPAM’s with DP of about 300 and meso dyad content, m, of 45% and 66%, LCSTs of 304.2 and 290.1 K were found, respectively,10 while polymer chains with m higher than approximately 70% are not soluble in water.10,13 Stereoregularity also affects the solubility of low DP polymers; indeed, the PNIPAM 56-mer with an m value of about 84% is water-insoluble across the temperature range 5−45 °C.14 The decrease of water affinity of isotactic-rich PNIPAMs leads to different kinds of self-assembly. PNIPAMs with m values from 50% to 59% and DPs of a few hundred residues were shown to form an intermolecular polymer-chain network in 5% wt aqueous solutions below the LCST.15 Such polymer networks are considered the cause of the acceleration of the Received: February 8, 2016 Revised: March 29, 2016 Published: March 31, 2016 3765

DOI: 10.1021/acs.jpcb.6b01339 J. Phys. Chem. B 2016, 120, 3765−3776

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The Journal of Physical Chemistry B

This work aims to explore, by means of molecular dynamics (MD) simulations, the structural and dynamical features underlying the tacticity-dependent solution behavior of PNIPAM in water, with a particular reference to the contribution of isotactic content. Can a local stereoregularity favor the intramolecular hydrogen bonding, HB, at the expense of HB with water? Why is the increased association ability of isotactic-rich polymer exhibited mainly at an interchain level, rather than intramolecularly? Is the association between residues driven by hydrophobic interactions and/or HB? Answering such questions needs a representation with atomic detail for both polymers, to adequately represent the stereochemistry, and solvent, to model hydrophobic effects. The high computing costs of atomistic simulation limit the DP of the model chain, especially if the infinite dilution condition is modeled. In this study we considered the PNIPAM oligomer with 30 repeating units, whose length corresponds to about 1− 2 Kuhn segments of atactic PNIPAM in the water-soluble state, as roughly evaluated by the estimate of the characteristic ratio of high DP single chains.23,24 Oligomers with similar DPs were used in previous PNIPAM MD simulation studies, indicating that the single chain coil−globule transition can be detected on this length scale.25,26 Two 30-mers with meso dyad content of 45% and 59%, corresponding to the stereochemical composition of the samples with the lowest and highest isotactic content, respectively, of ref 22, were built by assuming a Bernoullian distribution of isotactic and syndiotactic units. The single chain solution behavior of these stereoisomers was investigated at high dilution at 283 and 323 K, below and above the LCST of the corresponding atactic oligomer, on a time scale of hundreds of nanoseconds. The comparison of the results reveals structural details on polymer conformation and hydration pattern and characteristics of water dynamics as a function of PNIPAM stereochemistry.

phase separation in meso-dyad-rich PNIPAMs aqueous solutions above the transition temperature.15 The linear homopolymer with a DP of about 1000 and m of 64% is soluble in water at low temperatures, but it undergoes a reversible sol-to-gel transition by increasing temperature, in the investigated concentration interval of 1.8−6.0 wt %. With a further temperature increase the clouding behavior of the hydrogel can be observed, indicating the transition to an insoluble state.16 The formation of a physically cross-linked hydrogel, not occurring for corresponding atactic PNIPAMs, indicates that isotactic sequences are responsible for junctions and that interchain interactions prevail onto intrachain ones when the gel phase is stable.16 This association ability is exhibited also on a nanoscale by A−B−A stereoblock copolymers, with blocks consisting of atactic or isotactic-rich PNIPAMs. In 0.1 and 0.5 wt % aqueous solutions the copolymers spontaneously form micelles of different morphologies, depending on the chain composition.17,18 Chemically cross-linked hydrogels of isotactic-rich PNIPAM were characterized in comparison to not stereocontrolled hydrogels.8,13 Lower swelling ratios and higher deswelling rates below and above the VPTT, respectively, were found, coherently with that observed for the linear isotactic-rich homopolymer in solution. The increase of racemo dyad content has the opposite effect on PNIPAM water affinity, as compared to that of meso dyad content. Syndiotactic-rich PNIPAMs with 17% < m < 25% and low polydispersity are readily soluble, and their LCST is about 4 K higher than that of the atactic polymer.19 A similar increase of LCST is reported for a syndiotactic-rich PNIPAM with m = 29% and DP of about 800.11 The rationale of the modulation of PNIPAM water affinity by stereochemistry is under investigation. Experimental and computing studies of PNIPAM dimers and trimers in aqueous solution showed that meso dyads are less hydrophilic than racemo dyads.20,21 The difference of the hydration free energy between meso and racemo dimers, estimated by means of measurements of partition coefficient between water and chloroform, is 1.2 kJ mol−1. Molecular mechanics calculations indicated that the intramolecular interaction is stronger for the meso than for the racemo dimer, while the latter is advantageous in terms of the hydration free energy and conformational entropy.20 Molecular dynamics and metadynamics simulations of trimer stereoisomers in water suggest the syndiotactic sequence owns a more favorable conformational entropy than the isotactic sequence.21 These results indicate that the solution behavior of PNIPAM could be sensitive to tacticity also when the stereoregular regions have a length limited to two or three repeating units. For PNIPAMs with DP of about 300 residues, a series of scattering experiments revealed that the meso/racemo dyad ratio, in the m range 46%−58%, does not affect the static structure or the shrinking behavior of the single chain, but strongly affects the aggregation behavior. The PNIPAMs with low meso content suddenly associate around the phase separation temperature, while those with high meso content gradually aggregate with increasing temperature.22 According to these findings, the stereoregularity of the polymer chain has a scarce influence on the conformational features of PNIPAM in conditions of high dilution, for a meso dyad content from 46% to 58%. On the contrary, a relevant difference is produced on the intermolecular association.

2. SIMULATION PROCEDURES Various MD simulation studies of PNIPAM based systems can be found in the literature; however, in many of them the tacticity of the model used is not specified.27−31 In our best knowledge, this is the first MD simulation work specifically addressing the effect of stereoregularity on PNIPAM oligomers solution properties. To describe the polymer we used the force field OPLS-AA32 with the modifications of Siu et al.,33 that was recently shown to properly model the solution behavior of the syndiotactic 30-mer.34 The TIP4P/2005 model was selected for water,35 since it can reproduce the experimental temperature dependence of several properties of water, including density. The chemical structure of the 30-mer and the detailed stereochemistry of the oligomers studied are reported in Scheme S1 and Figure S1 of the Supporting Information, SI. In this work we modeled the PNIPAM stereoisomers with meso dyad content of 45% and 59%, hereafter named m45 and m59, respectively. In the design of the structure the distribution of isotactic and syndiotactic dyads was assumed to be Bernoullian. The chain conformation of the starting structure was obtained by imposing on the backbone dihedral angles values corresponding to states of minimum conformational energy for the dyads composing the oligomers.36,21 The sequence of backbone conformational states, together with the structure of the oligomers at the begin of simulations, is shown in Figure S2 of the SI. The PNIPAM 30-mer was centered in a cubic box of 9 nm side, oriented along a cube diagonal to maximize the distance between periodic images and having undergone energy 3766


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The Journal of Physical Chemistry B minimization in vacuo with tolerance of 10 kJ mol−1 nm−1. Then it was hydrated with about 23 000 TIP4P/2005 water molecules. A further minimization of energy with tolerance of 100 kJ mol−1 nm−1 was carried out, and the resulting system was used as initial configuration of the simulations both at 283 and 323 K. In these conditions we mimic the single chain behavior of PNIPAM oligomer in high dilution condition below and above the LCST. MD simulations were carried out in the NPT ensemble for 180 and 120 ns at 283 and 323 K, respectively. The leapfrog integration algorithm37 with a 2 fs time step, cubic periodic boundary conditions, and minimum image convention were used. The LINCS procedure was applied to constrain length of bonds involving H atoms.38 The temperature was controlled with the velocity rescaling thermostat coupling algorithm, with a time constant of 0.1 ps.39 The pressure was maintained at 1 atm by the Parrinello−Rahman approach, using a time constant of 2 ps.40,41 Electrostatic interactions were calculated by the smooth particle-mesh Ewald method,42 with the cutoff of nonbonded interactions being set to 1 nm. The last 80 ns of trajectory were considered for analysis, with a sampling frequency of 0.2 frame/ps. Computing activity was carried out within the GROMACS software environment (version 5.0.4),43,44 and the graphic visualization was done using the molecular viewer software package VMD.45 In the following parts of this section, we report some information about the procedures used for the trajectory analysis. The solvent accessible surface area, sasa, of a solute molecule is the surface of closest approach of the centers of solvent molecules where both solute and solvent are represented by hard spheres. Computationally, this surface is defined as the van der Waals envelope of the solute molecule expanded by the radius of the solvent sphere about each solute atom center.46 In this work the sasa of PNIPAM stereoisomers was evaluated using a spherical probe with radius of 0.14 nm and the values of van der Waals radii of the work of Bondi.47,48 The distributions of the values of radius of gyration, s, and of sasa, of PNIPAM oligomers were calculated with a bin of 0.01 nm and 0.1 nm2, respectively. The hydrogen bonding was studied by analyzing the trajectory for the occurrence of this interaction, adopting as geometric criteria an acceptor−donor distance (A···D) lower than 0.35 nm and an angle Θ (A···D−H) lower than 60°. The HB dynamics for an ensemble of donor and acceptor moieties was investigated by calculating the normalized intermittent time autocorrelation function, described by Rapaport49 and Luzar,50 where the correlation of a particular donor−acceptor pair is evaluated irrespective of possible prior hydrogen bond breaking and reforming events. The HB lifetime was evaluated by integration of the corresponding HB autocorrelation function. The ensemble of water molecules of the first hydration shell, fhs, was sampled by selecting molecules having the oxygen atom, OW, at a distance from nitrogen, N, or oxygen, OC, or methyl carbon atoms of PNIPAM, lower than the first minimum distance of the corresponding radial distribution functions with OW atoms. Such distances are 0.35 nm for fhs of N and OC atoms, and 0.54 nm for fhs of methyl carbon atoms of isopropyl groups. A water molecule was considered in the fhs of PNIPAM when it is within the fhs of at least one of these PNIPAM atoms.

The structure of the ensemble of fhs water at time t was analyzed by calculating the radial distribution function between OW atoms, rdfOW‑OW,fhs(r), that participate in the fhs at this time. To compare the results obtained at different times, the rdfOW‑OW,fhs(r) is multiplied by the number of water molecules in the fhs and divided by the box volume at the corresponding time frame. At each time frame the HB between water molecules of the fhs was analyzed. The distribution of values of the number of HBs per water molecule, NwwHB,fhs, was calculated with a bin of 0.01. The autocorrelation function of HBs formed within the fhs water ensemble was calculated in trajectory blocks of 5 ns within the production run. At the aim to characterize the structural organization of water in contact with PNIPAM, we defined the molecular surface concentration of hydration water, scOW,fhs, parameter, according to eq 1: scOW,fhs(t ) =

NOW,fhs(t ) sasa(t )

(1)

Here NOW,fhs(t) and sasa(t) are the number of fhs water molecules of the whole oligomer and its solvent surface accessible area, respectively. The distribution of scOW,fhs values was calculated with a bin of 0.01. The mobility of water in the surrounding of polymer was analyzed by labeling the water molecules of the fhs in the configuration at time t0 and then calculating the fraction of these water molecules, FWfhs, with still residency inside the fhs shell at t > t0. The FWfhs(t) time decay is caused by the exchange of the water molecules in the first hydration shell with the more external water molecules, due to the diffusion motion of the solvent. The FWfhs(t) time behavior was evaluated for intervals of 10 ns within the production run. The matrix of the mean smallest distances between atoms of pairs of residues was calculated with a time average of 2 ns along the production run. The 40 images of the map were collected in a movie, displaying the time behavior of contacts between residues. The residues located within an isotactic sequence were labeled on the diagonal of the matrix, with the aim to highlight a preferential connectivity.

3. RESULTS AND DISCUSSION 3.1. m45 System. First we consider the behavior of m45 oligomer, that, having a dyad composition near to that of PNIPAM synthesized without stereoselective agents,7 can be discussed on the basis of experimental findings of atactic PNIPAM. Turbidity measurements showed LCST values of about 313 K for diluted aqueous solutions of not stereoregular oligomers with DP around 30;4 then, the temperature conditions of 283 and 323 K, used for simulations, correspond to the soluble and insoluble state in the phase diagram, respectively. The radius of gyration and the solvent accessible surface area, defined in section 2, are structural parameters typically considered to monitor the water affinity of a polymer in aqueous solution. The distributions of s values for m45 at 283 and 323 K, below and above the LCST, respectively, are shown by red and purple lines in Figure 1. The distributions of sasa values are reported in Figure 2, using the same color code as in Figure 1. At the lowest temperature both s and sasa distributions are bimodal, with the less populated state, characterized by higher s 3767


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Figure 1. Distributions of values of radius of gyration for m45 at 283 and 323 K (red and purple, respectively) and for m59 at 283 and 323 K (blue and green, respectively). Full lines: 283 K. Dotted lines: 323 K.

Figure 3. Trajectory snapshots showing the most populated chain conformation of m45 at 283 K (a) and 323 K (b), and m59 at 283 K (c) and 323 K (d). Backbone chain is colored in green. Hydrogen atoms and water molecules are omitted.

located at specific distances along the chain are reported. Table 2 shows the total average number of HBs between PNIPAM and water, together with the individual contributions to hydrogen bonding of N and OC atoms. The intramolecular hydrogen bonding of m45 is scarcely affected by temperature. HBs between near-neighboring residues correspond to the highest fraction of this interaction (Table 1). A decrease of about 12% for the HBs between PNIPAM and water is observed after the transition (Table 2), with the relative decrease being slightly higher for HBs formed by N atoms. The coil-to-globule transition of PNIPAM, followed by intermolecular association, in aqueous solution was investigated by Fourier transform infrared spectroscopy, and about 13% of the CO groups is estimated to form intra- or interchain hydrogen bonding in the globule state.51 The results on HB between PNIPAM residues in m45 at 323 K, with an average of 0.13 HBs per PNIPAM residue, are in agreement with the experimental finding. Spectroscopic methods showed that below the LCST each amide group of PNIPAM is hydrated by two (to three) water molecules as a result of hydrogen bond formation.52,53 The value of 2.3 ± 0.1 HBs per residue formed by m45 with water at 283 K (Table 2) compares well with the experimental estimate. A Compton scattering study on the molecular-level structural changes of PNIPAM in aqueous solution highlighted a reduction of the amount of HBs formed by polymer after the coil-to-globule transition; however, the change in the number of hydrogen bonds was not quantified.54 The hydrogen bonding between polymer and water in chemically cross-linked PNIPAM based nanohydrogels has been investigated by means of UV resonance Raman spectroscopy.55 At low temperature the amide groups of PNIPAM are predominantly fully water hydrogen bonded, whereas in the collapsed state one of the two hydrogen bonds formed by the carbonyl oxygen is lost. The NH−water hydrogen bonding, however, remains unperturbed by the

Figure 2. Distributions of values of solvent accessible surface area for m45 at 283 and 323 K (red and purple, respectively) and for m59 at 283 and 323 K (blue and green, respectively). Full lines: 283 K. Dotted lines: 323 K.

and sasa values, corresponding to almost fully extended chain conformation. By comparing the distribution of radius of gyration of m45 at 283 K with that obtained for the syndiotactic 30-mer at 280 K in a MD simulation study,34 the smaller propensity of m45 to assume extended conformations in aqueous solution can be noted. This result is in agreement with the higher hydrophilicity of the dyad syndiotactic, experimentally observed at 298 K.20 The temperature induced coil− globule transition of m45 is clearly indicated by behaviors of Figures 1 and 2, showing a marked reduction of s and sasa values at increasing temperature. Overall, the chain behavior of m45 corresponds to that expected for the atactic PNIPAM, with a ratio between the average values of s and sasa in the insoluble and soluble states of 0.749 ± 0.001 and 0.848 ± 0.001, respectively. A trajectory snapshot illustrating the structure of the most probable chain conformation state of m45 at 283 and 323 K is reported in Figure 3a,b, respectively. The difference of the chain conformation between the coil and globule states can be related to variations in polymer− polymer and polymer−water interactions. Information on the intramolecular hydrogen bonding of m45 at 283 and 323 K is given in Table 1, where the average number of HBs per PNIPAM residue and the fraction of HBs between residues 3768


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The Journal of Physical Chemistry B Table 1. Polymer−Polymer Hydrogen Bonding fraction of HBs between selected pairs of residues m45 m59

283 323 283 323

no. of HBs per residuea

n − (n + 1)b

n − (n + 2)c

n − (n + 3)d

n − (n + 4)e

n − (n + 5)f

n − (n + k)g k > 5

± ± ± ±

0.58 0.56 0.47 0.56

0.11 0.11 0.20 0.12

0.19 0.16 0.33 0.26

0.00 0.04 0.00 0.01

0 0.00 0 0.00

0.12 0.12 0.00 0.05

K K K K

0.13 0.13 0.10 0.13

0.07 0.07 0.03 0.07

a Time average and standard deviation over the production run. bFraction of HBs formed between adjacent residues. cFraction of HBs formed between residues separated by 1 repeating unit. dFraction of HBs formed between residues separated by 2 repeating units. eFraction of HBs formed between residues separated by 3 repeating units. fFraction of HBs formed between residues separated by 4 repeating units. gFraction of HBs formed between residues separated by more than 4 repeating units.

Table 2. Polymer−Water Hydrogen Bonding and Features of Water within the First Hydration Shella

m45

283 K

323 K

m59

283 K

323 K

av no. of HBs (per PNIPAM residue)

av no. of water molecules within the fhs (per PNIPAM residue)

av lifetime of HBs between water molecules in the fhs, τw‑wHB,fhs (ps)e

half exchange time of fhs water ensemble, τfhs,0.5 (ps)

± ± ± ± ± ± ± ± ± ± ± ±

12.7 ± 0.4

33 ± 5

119 ± 22

2.3 1.63 0.72 2.03 1.47 0.58 2.50 1.73 0.76 2.20 1.57 0.63

0.1b 0.07c 0.02d 0.07b 0.03c 0.02d 0.03b 0.02c 0.02d 0.03b 0.03c 0.02d

10.4 ± 0.3

44 ± 4

12.3 ± 0.4

35 ± 6

10.9 ± 0.3

122 ± 15

46 ± 6

a

Errors estimated by blocking method. bTotal polymer−water HBs. cHBs between water and CO. dHBs between water and N−H. eBlocks of 5 ns.

Figure 4. Radial distribution functions between OC and OW atoms (left), between nitrogen, N and OW atoms (center), and between carbon atoms of methyl groups and OW atoms (right), for m45 at 283 and 323 K (red and purple, respectively) and for m59 at 283 and 323 K (blue and green, respectively). Time average over 10 ns.

collapse of the PNIPAM network.55 We can compare the simulation results with these experimental findings, by taking into account that the experimental system is a hydrated covalent network with a high cross-link density and the simulation system is a freely diffusing chain in solution. The average number of polymer−water HBs per PNIPAM residue obtained for m45 at 283 K is qualitatively in agreement with the experimental estimate performed for the nanogel in the swollen state. However, the selective decrease of HBs involving CO groups, observed in the nanogel above the volume phase transition temperature, does not find a correspondence in our simulations. Indeed a quite similar decrease of HBs for both CO and NH groups can be noted, comparing results at

283 and 323 K (second column of Table 2). This discrepancy can be explained by considering the topological constraints of PNIPAM chains in the nanogel, caused by covalent junctions of the polymer network. Such constraints can modify the dehydration modality of the polymer in the hydrogel, as compared to that of the single chain in solution. The hydration pattern of m45 was analyzed by calculating the radial distribution functions between PNIPAM atoms and water oxygen atoms. The radial distribution functions between OC and OW atoms, rdfOC‑OW(r), between nitrogen, N, and OW atoms, rdfN‑OW(r), and between carbon atoms of methyl groups, Me, and OW atoms, rdfMe‑OW(r), are reported in Figure 4. 3769


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hydration water in the transition from a relaxed coil to an elongated conformation is estimated as 5 kJ per mol of PNIPAM residues. By analyzing the dependence of the hydrogen bonding of fhs water on the radius of gyration, shown in Figure S3 of the SI, an increase of HBs with the chain elongation can be noted. The number of HBs formed by water increases by about 1.5 per PNIPAM residue moving from a coiled to an extended chain, which implies a favorable enthalpy contribution to the ΔG of elongation. This finding leads us to conclude that the free energy cost estimated by AFM is attributable to an unfavorable entropy contribution, as the elongation generates an increase of the interface between water and PNIPAM hydrophobic groups and therefore of the water structuring. The relaxation time of the exchange or dehydration process of water molecules associated with PNIPAM chains in aqueous solution was estimated by dielectric relaxation experiments. The value of 23 ps is obtained at 298 K, with an activation energy of 25 kJ/mol,56 and then a relaxation time of 39 ps at 283 K can be estimated according to the Arrhenius law. The dynamics of water within the oligomer fhs was studied both calculating the lifetime of water−water HBs, τw‑wHB,fhs, reported in Table 2, and directly monitoring the exchange of such molecules with the more external water molecules, due to the diffusion motion of the solvent. The value of τw‑wHB,fhs for m45 at 283 K is in satisfactory agreement with the experimentally obtained relaxation time. Figure 6a (red curve) displays the time behavior of the number fraction of water molecules still residing in the fhs at a time t > t0, with t0 being the sampling time of the original fhs water ensemble (see section 2), for m45 stereoisomer at 283 K. The decay of curves in Figure 6 highlights the exchange dynamics of water in the surrounding of PNIPAM, showing that about 20% of water molecules remain confined within the first hydration shell, irrespective of temperature. The value of the time for the 50% refresh of fhs solvent, τfhs,0.5, is reported in Table 2. Such value is higher than τw‑wHB,fhs (Table 2), as τfhs,0.5 is related to the collective mobility of the water ensemble. The behavior of the curves in Figure 6a is clearly not monoexponential. Within the initial 500 ps, the decay is wellfitted by a linear combination of two exponential functions with an offset corresponding to the fraction of not exchangeable fhs water molecules (Equation S1 and Figure S4 of the SI). The ratio between the characteristic times of the slower and faster process is about 20, and the fractions of water molecules involved in the two exchange modalities are similar (Table S1 of the SI). The presence of two kinetically different contributions to the exchange of water confined in the fhs can be explained by considering the different interaction of water with hydrophilic and hydrophobic groups of PNIPAM and/or the possibility of alternative paths to exit the shell, i.e., transversely and longitudinally to the chain contour. It is noteworthy that the value of the characteristic time of the faster process (Table S1 of the SI) is comparable with the lifetime of HBs between water molecules of the fhs (Table 2). A still controversial issue of the temperature induced PNIPAM transition in aqueous solution is the extent of polymer dehydration from the coil to globule state. According to the analysis of overall water in the fhs, we find a dehydration of about 18%, larger than the loss of water bound to a PNIPAM hydrophilic group, which is about 12%, Table 2. This feature is confirmed by the behavior of radial distribution functions in Figure 4, where rdfMe‑OW(r) shows a remarkable decrease of the

These functions show a complex hydration structure, with at least three hydration shells at both temperatures. The number of OW atoms included in the first hydration shell of PNIPAM atoms, NOW,fhs, was directly measured, as described in section 2, and the average NOW,fhs values, normalized per residue, are reported in Table 2. It is noteworthy that the NOW,fhs parameter quantifies the exposure to water of both hydrophilic and hydrophobic moieties of PNIPAM. The number of water molecules within the PNIPAM fhs at 283 K, about 13 molecules per residue, qualitatively agrees with the estimate of about 11 molecules per residue obtained for the hydration number of PNIPAM below the LCST by dielectric relaxation measurements.56,57 In these works the authors suggest that such water molecules, directly hydrating the polymer, are involved in a network of HBs stabilizing the solvation shell. A similar picture of the PNIPAM hydration was previously proposed by Okada and Tanaka, which theoretically derived the phase diagram of PNIPAM in water by postulating a cooperative hydration pattern of the polymer.58 On the basis of the Okada and Tanaka model,58 we explored the connectivity between water molecules directly hydrating the polymer by analyzing the hydrogen bonding of the ensemble of water molecules in the fhs. The distribution of values of the number of HBs formed between water molecules belonging to the PNIPAM fhs, normalized per water molecule, Nw‑wHB,fhs, is shown in Figure 5.

Figure 5. Distribution of values of the number of water−water HBs within the PNIPAM fhs, for m45 at 283 and 323 K (red and purple curves, respectively) and m59 at 283 and 323 K (blue and green curves, respectively). The HB number is normalized per water molecule.

A narrow, monomodal distribution is obtained for m45 at 283 K, with the maximum at the Nw‑wHB,fhs value of about 1.4 HBs per molecule. In a perfect network formed by water molecules distributed onto a surface where each molecule is hydrogen bonded to three near-neighboring molecules, the number of HBs per molecule is 3/2. Therefore, the distribution of Nw‑wHB,fhs values of the m45 stereisomer in the coil state suggests that the water in the surrounding of polymer forms a connected hydration layer with 3-fold junctions and few defects. Such a simulation result provides a quantitative counterpart to the left image in Scheme 1 of ref 56. The analysis of the hydrogen bonding in the fhs water of m45 at 283 K is suited to a comparison with the results of an atomic force microscopy, AFM, investigation of atactic single chain PNIPAM at high DP in aqueous solution at 298 K.59 In this work the free energy variation for the rearrangement of 3770


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Figure 6. Time behavior of the number fraction of water molecules residing in the fhs at 283 K (a), for m45 (red) and m59 (blue), and at 323 K (b), for m45 (purple) and m59 (green). The initial decay is shown in the inset.

first peak high moving from 283 to 323 K, as compared to rdfOC‑OW(r) and rdfN‑OW(r). Therefore, the rearrangement of the distribution of hydrophobic isopropyl moieties has a major contribution in the decrease of the water−polymer interface related to the coil−globule transition. Such simulations results are in agreement with the conclusions of the experimental study of Pelton,60 stating that oxygen- and nitrogen-rich domains of PNIPAM are hydrophilic above and below the LCST and isopropyl groups are surrounded by water or in contact with both water and polymer segments below or above the LCST, respectively. Figure 5 shows that above the LCST the PNIPAM hydration layer is less structured than below the LCST, as the hydrogen bonding between water molecules decreases from 283 to 323 K. By considering the number of water molecules in the fhs per PNIPAM residue, we can estimate an average decrease of 3.5 water−water HBs per PNIPAM residue in the transition from the coil to the globule state. By addition of the decrease of polymer−water HBs, about 0.3 HBs per residue, a total decrease of 3.8 HBs per residue is generated in the surrounding of the polymer for the coil−globule transition. 3.2. m59 System and m45−m59 Comparison. The results of m45 simulations highlight some key features of the solution behavior of PNIPAM, with a satisfactory agreement with available experimental data. Having that as a reference, we analyze the properties of m59 system. The distributions of values of radius of gyration for the m59 stereoisomer are reported in Figure 1. At both 283 and 323 K (blue and green lines, respectively) a bimodal distribution is obtained, with a drop of s values at the highest temperature. The distributions of values of solvent accessible surface area of m59, reported in Figure 2, show a trend with temperature which is coherent with that of s distributions. The reduction of s and sasa values indicates a decreasing of affinity for water at increasing temperature, as expected for PNIPAM and observed for m45. However, a remarkable difference in the average size of the oligomers in the soluble state can be noted by comparing the distribution of s values for m45 and m59 at 283 K. The most populated conformer of the isotactic-rich stereoisomer, shown in Figure 3c, has an s value of about 1.1 nm, lower than the average s of m45. The second populated state of m59, with s around 1.3 nm, has a radius of gyration similar to that of the preferred conformer of m45, but conformational states with s higher than 1.4 nm are absent for m59. We can exclude that the preference of m59 for less extended chain conformations is

intrinsically caused by the stereochemistry of the vinyl chain, because of the predominance of isotactic dyads. Indeed, Flory et al. showed that isotactic polymers in the minimum energy conformation state form elongated structures corresponding to 31 helices,36 with high s and sasa values. The presence of such helical regions, that in PNIPAM can be stabilized by intramolecular HBs between amide groups of n and n + 3 residues, has been proposed to explain the lowering of the glass transition temperature of stereoregular PNIPAMs at increasing isotactic dyads content.61 Therefore, the chain behavior of m59 at 283 K is specifically governed by the interaction with water and suggests a lower hydrophilicity as compared to m45 stereoisomer. The comparison between the radial distribution function between methyl carbon atoms of PNIPAM isopropyl groups, rdfMe‑Me(r), of m45 and m59 systems, shown in Figure S5 of the SI, highlights the greater propensity of m59 to assume conformations where the distance between hydrophobic methyl groups is reduced, typical of a less hydrophilic chain. PNIPAMs with dyad compositions in between m = 46% and m = 58% and DP of about 300 form thermodynamically stable diluted aqueous solutions below 292 K. In these conditions such PNIPAM stereoisomers exhibit a Gaussian coil behavior, evidenced by the value of about 1.5 for the ratio radius of gyration/hydrodynamic radius.22 At the temperature of 283 K and concentration of 0.2% (w/w), comparable hydrodynamic radii are measured, irrespective of the meso/racemo dyad ratio.22 By extending the last experimental finding to the 30mers of this work, the results in Figure 1 show a discrepancy, since at 283 K chain conformations with lower radii of gyration are detected for m59 as compared to the other stereoisomer. However, the not-Gaussian character of the distributions of s values in Figure 1 suggests that the extrapolation of the single chain behavior of ref 22 can admit deviations, because of the limited DP of our models. The absence of long-range interactions and the higher contribution to the torsional freedom by the external chain regions allow for a greater flexibility of the oligomer, as compared to the high DP macromolecule, affecting the balance between hydration and conformational free energy contributions, which finally determines the average size of the chain in solution. Therefore, the ratio between the sizes of stereoisomers with different meso/racemo dyad ratios can change depending on the DP, at least in the range of low molecular weight PNIPAMs. The sasa distributions of m59 and m45 at 283 K, Figure 2, are more similar as compared to s distributions, although the 3771


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Figure 7. Inter-residue contact map of m45 (left), m58 (right) at 283 K. Time average in the last 2 ns trajectory.

Figure 8. sasa values for residues of m45 (left) and m59 (right) at 283 K as a function of the residue index. Error bars are standard deviations. Time average over 10 ns. The stereochemistry of each residue is represented on the top, using the nomenclature of ref 36 (see Figure S1 of SI).

states with the greatest sasa values, visible for m45, are not present for m59. To evaluate whether the isotactic regions of the chain are directly responsible of the increased intramolecular connectivity of m59 at 283 K, we calculated the matrix of the mean shortest distances between pairs of residues, as described in section 2. Figure 7 displays the contact maps of m45 and m59 at 283 K obtained with a time average on the last 2 ns, using a color scale to indicate the distance value. The dots on the diagonal of matrix label the residues which are internal to isotactic sequences. The time evolution of these maps is shown in video 1 and video 2, presented as web-enhanced objects, WEOs. The contacts between residues that are topologically distant are visible as orange-yellow spots far from the diagonal of the map. During the trajectory the chain regions implicated in short contacts change, both for m45 and m59, and the higher connectivity of the isotactic-rich stereoisomer can be noted. Looking for a correlation between intrachain junctions and local tacticity, it can be noted that several contacts in m59 involve residues of isotactic sections (see WEOs). Figure 8 displays the sasa for the single residues of each oligomer at 283 K, with a time average in a trajectory interval of

10 ns selected to sample the most populated chain conformer. The stereochemistry of residues sequence is reported in Figure 8, at the aim to associate the residue index to the local tacticity of the chain. The behavior of sasa values in Figure 8 is quite erratic, with an expected greater sasa for chain end residues. It is noteworthy that, for both m45 and m59, the lowest sasa is shown by the initial residue of the longest isotactic segment, formed by five repeating units and placed in the middle of the chain. The information from Figure 8 is complementary to that from interresidue contact maps, since a higher propensity of a residue to establish contacts can correspond to a lower average solvent surface accessible area. This is indeed observed for residue 24 of m59 at 283 K (see video 2 and Figure 8). Intrachain hydrogen bonding is typically related to the conformation of a polymer chain. Table 1 describes some features of polymer−polymer HBs of m59, as compared to m45. The overall intramolecular HB capability of the stereoisomers is the same, within errors. However, the analysis of the distribution of HB’s formed by pairs of residues at specific distances along the chain reveals that in m59 the HBs between n and n + 3 residues are favored, as compared to m45. 3772


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Figure 9. Not normalized radial distribution functions between OW atoms of the fhs at 283 K for m45 (left) and m59 (right). Overlay of results at five time frames 10 ns apart.

This finding agrees with the conformational preference of the isotactic-rich stereoisomer backbone, as previously discussed. The hydrogen bonding with water of m59 is comparable to that of m45, with a slightly higher HB ability of CO groups for the former oligomer (Table 2). Then the chain behavior of m59 is not related to decreased solvation of the hydrophilic groups. Figure 4 offers a comparison of the hydration structure for the two stereoisomers. At 283 K the radial distribution functions between PNIPAM atoms and water oxygen of m45 and m59 are similar, especially in the first hydration shell. Accordingly, the average number of water molecules in the fhs does not change with stereochemistry (Table 2). A correlation between the conformational differences of m45 and m59 and their hydration pattern can be found by analyzing the structural organization and dynamics of water molecules in the surroundings of the polymer. To explore these characteristics we selected the ensemble of water molecules of the PNIPAM first hydration shell at specific time frames and analyzed the OW−OW radial distribution function and water− water hydrogen bonding, as described in section 2. The results are shown in Figures 9 and 5, respectively. For both stereoisomers the behavior of the curves in Figure 9 shows an organization in the ensemble of fhs water molecules, extending to distances equal to about half of the average radius of gyration. The distribution curves of Figure 5 provide an atomistic counterpart to the cooperative hydration model of PNIPAM in aqueous solution,58 which asserts that sequential hydrogen bonds are formed along the polymer chain due to the cooperative interaction between the nearest-neighboring bound water molecules. The values of HB’s number per water molecule of Figure 5 at 283 K are compatible with a network of water extending on a surface around PNIPAM, where each water molecule forms about one HB with three adjacent molecules. Figure 5 shows a difference between m45 and m59 in the structuring of the f hs water at 283 K, since the distribution curve for m59 is slightly translated toward higher abscissa values. To highlight further differences in the organization of this water ensemble we considered the surface concentration of water molecules in the first hydration layer surrounding PNIPAM, scOW,fhs, defined in section 2. Such property was dynamically evaluated as the ratio of the total number of water molecules in the fhs to the value of the sasa. The results of this analysis, shown in Figure 10, reveal that at 283 K the surface

Figure 10. Distribution of values of the surface concentration of water molecules in a monolayer around PNIPAM. m45 at 283 and 323 K (red and purple symbols, respectively); m59 at 283 and 323 K (blue and green symbols, respectively).

concentration of water molecules in the surrounding of polymer is lower for m59, as compared to m45. By summarizing the features of the hydration pattern from Figures 5 and 10, we can conclude that, in the stereoisomer with higher content of meso dyad, water molecules of the first hydration shell have a slightly higher hydrogen bonding and a lower density on the surface around the polymer. Such characteristics are typical of the hydration of hydrophobic moieties, which is disfavored/favored by entropy/enthalpy, respectively, and where the lower local density of water allows for HB formation. According to this analysis and considering that the HB capability of amide groups with water is not diminished with the increase of the meso dyad content, the solution behavior of m59, as compared to m45, is governed by hydrophobic interactions. We considered whether the structural differences of the fhs water between m45 and m59 are accompanied by differences in dynamical properties. The kinetics of the process of exchange of the water molecules constituting the first hydration shell for m45 and m59 at 283 K is compared in Figure 6a. Table 2 compares the values of τfhs,0.5 and τw‑wHB,fhs, the time for the exchange of half of the first hydration shell and the water− water HB lifetime in the fhs, respectively, obtained for the stereoisomers. An influence of meso dyad content on these characteristic times of water mobility in the surrounding of PNIPAM is not apparent. 3773


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Gaussian coil, because of the short chain length. The low DP polymer can own a greater flexibility, as compared to the high DP macromolecule, for the absence of long-range interactions; therefore, the balance between hydration and conformational free energy contributions can lead to different ratios between the chain size of stereoisomers depending on the DP. Moreover, we cannot exclude that the assumption of the Bernoullian sequence of dyads, used in simulations, does not fully represent the stereochemistry of samples of ref 22, where tacticity is not characterized beyond the dyad composition. However, the study of the influence of the distribution of the racemo/meso dyads (random or block) is out of the scope of this work. Simulation results display that, above the LCST, the stereochemistry of PNIPAM little affects the chain conformation and hydration in the investigated range of meso dyads content. This indicates that the modulation of hydration and conformational effects associated with the dyad composition is overtaken when the solvation free energy becomes very unfavorable. The behavior of stereocontrolled PNIPAM oligomers in more concentrated solution is under investigation by MD simulations, with the aim to characterize both the intra- and the intermolecular interactions of PNIPAM as a function of the racemo/meso dyad composition. These results will complete the picture on the influence of tacticity on the properties of this macromolecule in aqueous environment.

So far, we focused the comparison between the steroisomers below the LCST. At 323 K, above the LCST, the stereochemistry induced differences in solution properties are expected to be minor since in this condition the polymer is not soluble irrespective of tacticity. The distributions of the radius of gyration values at 323 K, Figure 1, are similar, and both stereoisomers are preferentially in the globule state. The most populated conformers for m45 and m59, Figure 3b,d, respectively, have the same radius of gyration and comparable solvent surface accessible areas. As compared to m45 results, the shift of the Γ(sasa) curve of m59 toward higher sasa values observed at 323 K, Figure 2, together with the population of states with larger s values, Figure 1, can be attributed to the formation of helix regions in the isotactic sections of m59, stabilized by HBs between n and n + 3 residues (Table 1). These elongated regions disfavor closely packed chain conformations and increase both the s and the sasa values of the globule state, allowing for a higher accessibility of OW atoms to PNIPAM carbonyl groups (left plot of Figure 4). The properties concerning the hydration at 323 K are little affected by the dyad composition, as shown by Figure 4 and by data in Table 2. A slightly lower organization of water molecules in the fhs at 323 K can be noted for m59 (Figures 5 and 10).

4. CONCLUSIONS This simulation study shows that the behavior of PNIPAM 30mer in diluted aqueous solution is sensitive to dyad composition, both in properties concerning the whole chain and the water interaction. At 283 K, a temperature condition where low DP PNIPAMs with meso dyad content lower than 84% are soluble,14 the isotactic-rich stereoisomer with m = 59% prefers chain conformations with radius of gyration and solvent accessible surface area lower as compared to the stereoisomer with m = 45%. Water molecules in the first hydration shell interact with hydrophilic groups of m59 and m45 to a similar extent; however, a slightly higher hydrogen bonding between solvent molecules of the first layer surrounding PNIPAM, together with a lower surface density, is found for the stereoisomer with larger content of meso dyads. These results are in agreement with experimental findings obtained for the compounds corresponding to PNIPAM meso and racemo, r, dyads. By measurements of partition coefficient in water/ chloroform mixture, a difference in the hydration free energy between m- and r- at 298 K of 1.2 kJ mol−1 was estimated, indicating that the meso dimer is less hydrophilic than the racemo dimer.20 From simulation results of m59 below the LCST we can infer the following: (i) The meso dyad is less hydrophilic than the racemo dyad also when embedded randomly in the oligomer chain. (ii) The difference in the hydration free energy between meso and racemo dyads in the 30-mer can compensate for the conformational energy cost of isotactic sections to assume folded states. PNIPAM samples having a dyad composition almost corresponding to that of m59 and m45 and DP of about 300 form thermodynamically stable diluted aqueous solutions below 292 K. Such PNIPAM stereoisomers exhibit a Gaussian coil behavior and display similar hydrodynamic radii at 283 K at the concentration of 0.2% (w/w).22 The extrapolation of these results to the oligomers of the present study, having DP 1 order of magnitude lower, has to be considered with caution. The characteristics of m45 and m59 do not correspond to the

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.6b01339. Details describing the structure, stereochemistry, initial chain conformations, and kinetics; scheme showing chemical structures; figures of relevant features including stereochemistry, initial conformations, starting structures, dihedral angles, and correlation of radius of gyration and hydrogen bonding of fhs water; and table of kinetic parameters (PDF). W Web-Enhanced Features *

Videos of time evolutions of inter-residue contacts of m45 and m59 are available in the online version of the paper.

■

AUTHOR INFORMATION

Corresponding Author

*Phone: +39 06 7259 4464. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We acknowledge the CINECA award under the ISCRA initiative, for the availability of high performance computing resources and support. Computing activity was carried out within the ISCRA C project HP10CDTIHL funded by SCAI SuperComputing Applications and InnovationCINECA. Mr. M. Borrelli is acknowledged for carrying out some preliminary simulations.

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REFERENCES

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