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B: Biophysics; Physical Chemistry of Biological Systems and Biomolecules

Factors Promoting the Formation of Clathrate-like Ordering of Water in Biomolecular Structure at Ambient Temperature and Pressure Sridip Parui, and Biman Jana J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b11172 • Publication Date (Web): 03 Jan 2019 Downloaded from http://pubs.acs.org on January 8, 2019

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The Journal of Physical Chemistry

Factors Promoting the Formation of Clathrate-like Ordering of Water in Biomolecular Structure at Ambient Temperature and Pressure Sridip Parui and Biman Jana * School of Chemical Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032 AUTHOR INFORMATION Corresponding Author: Biman Jana E-mail: [email protected]. Phone: +91 33 2473 4971.

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Abstract Clathrate-hydrate forms when a hydrophobic molecule is entrapped inside a water cage or cavity. Although biomolecular structures also have hydrophobic patches, clathrate-like water is found in only a limited number of biomolecules. Also, while clathrate-hydrates form at low temperature and moderately higher pressure, clathrate-like water is observed in biomolecular structure at ambient temperature and pressure. These indicate presence of other factors along with hydrophobic environment behind the formation of clathrate-like water in biomolecules. In the current study, we presented a systematic approach to explore the factors behind the formation of clathrate-like water in biomolecules by means of molecular dynamics simulation of a model protein, maxi which is a naturally occurring nanopore and has clathrate-like water inside the pore. Removal of either confinement or hydrophobic environment results in the disappearance of clathrate-like water ordering indicating a coupled role of these two factors. Apart from these two factors, clathrate-like water ordering also requires anchoring groups which can stabilize the clathrate-like water through hydrogen bonding. Our results uncover crucial factors for the stabilization of clathrate-like ordering in biomolecular structure which can be used for the development of new biomolecular structure promoting clathrate formation.


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Introduction Clathrate compounds are usually a binary mixture of two substances where a guest molecule is trapped inside the cage or lattice of host molecule.1,2 Substances like H2O, SiO2, Si, Ge etc which are able to form tetrahedral network in their pure crystal can also make clathrate structures in presence of suitable guest molecule.3 These substances are connected with each other and form a lattice-like structure with polyhedral cages with an appropriate cavity inside which a guest solute can fit. A unique feature present in these clathrates is that the guest molecules hardly interact with each other while strong interaction is found among host molecules in the tetrahedral lattice. Clathrate-hydrate is a crystalline solid of water in which non-polar molecule, usually gas molecule, is trapped inside the cages of hydrogen bonded water molecules. Large amount of natural gases is reserved on the ocean floor as the form of clathrate-hydrate4-6. Because of many practical purposes and applications4,7-10, thermodynamics and kinetics of clathrate hydrate in the context of its growth11-14, promotion15-17 and inhibition18-22 have become a fascinating topic in the field of physical chemistry also. Formation (or decomposition) of clathrate-hydrate is a first order phase transition. Though there are several proposed mechanisms for nucleation pathways for the formation of clathrate hydrate11-14, it is still an active field of research23. Clathrate-hydrates are formed at suitable temperature and pressure (typically at cold temperature and moderately high pressure). In general, guest molecules are needed to stabilize the clathrate. However, guest free clathrate has been synthesized for Ge24 and Si25. However, the synthesis of an empty clathrate is yet to be realized in laboratory. There are some computational efforts to make guest-free clathrate of water26,27. Molinero and coworker showed that empty clathrate of water can form but at high negative pressure.26 Bai et al reported an evidence of formation of guest-free clathrate inside a hydrophobic-slit but at temperature below the melting temperature of used water model TIP5P28.27 3 ACS Paragon Plus Environment


So, an empty clathrate at ambient temperature and pressure is unstable and difficult to detect or synthesize. Buchanan et al did not observe significant changes in water structure before clathratehydrate formation and after clathrate hydrate decomposition denying clear support of memory effect29-31.32 This indicates that in absence of guest molecule, clathrate cages would collapse at positive pressure. Interstitial guest molecules thus stabilize the clathrate cages by preventing the collapse of the clathrate cavity. Unlike ice hexagons, clathrate hydrates are largely composed of poly pentagonal rings. Structure of water in clathrate- hydrate is different from that of ice and liquid water in their cage structure26,33-36, bond orientation33,37and angular orientation34,38. There exist some water molecules which are not crystalline but have similar, however, not exact, orientational order with water in clathrate and these water molecules are referred to as clathrate-like water. Such clathrate-like water is observed in many biomolecular structures. Clathrate-like water molecules are usually used by antifreeze proteins (AFPs)39-45 and ice nucleating proteins (INPs)42,46 in their biomolecular recognition. As water is an integral part of cellular environment47-56, clathrate-like water plays important role in biomolecular recognition of AFPs and INPs. Observation of clathrate-like water in AFPs and INPs is not very surprising as their function is related to either ice growth inhibition or ice nucleation at cold temperature. However, clathrate-like order is also observed in other biomolecules other than AFPs and INPs.57-60 Alkanes like methane, propane etc which are analogous to the hydrophobic sidechains of AFPs and INPs form alkane hydrates. So hydrophobic hydration plays a crucial role in clathrate-like ordering in AFPs and INPs. Hydrophobic hydration at ambient temperature and pressure is generally associated with positive chemical potential and heat capacity changes (ΔCP) and negative enthalpy (ΔH) and entropy changes (ΔS).61 The classical view to explain the changes of 4 ACS Paragon Plus Environment

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these thermodynamics variables is that waters around hydrophobic molecule forms transient clathrate structure, commonly known as “iceberg” arising from enhanced hydrogen bonding of water.62,63 Hydrophobic hydration is thus accompanied by negative entropy change due to the increased ordering in the surrounding water of hydrophobic molecule and negative enthalpy change due to van der waals interaction between water and hydrophobic molecule. Positive ΔCP can also be explained by the increased ordering of hydration shell compared to bulk water.64 However, there are examples both in favor and in opposition of iceberg model.65-78 External stress can modulate hydrophobic hydration.78-101 Hydrophobic hydration gets enhanced at cold temperature78-86 and at elevated pressure87-91. Enhanced hydrophobic hydration at cold temperature and at high pressure may promote formation of clathrate-like ordering of water around hydrophobic regions of proteins. Clathrate-hydrate generally forms at cold temperature and high pressure. However, it has been shown that hydrates of Xe, THF form at ambient conditions.102-106 There has been an active research to elucidate the mechanism of formation of these clathrate hydrates, especially hydrate of THF107-115. Our system of interest for the present study is the biological systems, like AFPs and INPs, for which the hydrophobic sidechains are largely composed of carbon and hydrogen atoms and analogous to alkanes like methane, ethane, propane etc. But, if the hydrophobic principle for formation of clathrate-like water was the only governing factor, clathrate-like water would have been observed frequently in crystal structure of biomolecules as biomolecules have hydrophobic surfaces. Till date, presence of clathrate-like water has been noticed in a limited number of biomolecular structures. Additionally, although alkane-hydrates form at cold temperature and at moderately higher pressure, clathrate-like water in AFPs, INPs is observed at near-ambient temperature and atmospheric pressure. These indicate presence of other factors along with hydrophobic environment that promotes clathrate-like



ordering around some biomolecules. To determine the factors behind the formation of clathrate-like water in biomolecular structure, we have taken type 1 AFP maxi43 protein as our model system as it shows characteristic clathrate-like water even in absence of ice surface43,80. Maxi is a homo-dimeric protein. Its structure is unusual in the context of hydrophobic core principle as its core contains lot of water molecules (Figure 1A1).116 In comparison, core of Rop-dimer (Repressor Of Primer) is well packed and completely hydrophobic (Figure 1A2). Though computational studies of water structure of maxi were done80,117, molecular insights into the clathrate-like water in maxi are still unclear. In this study, we present a systematic approach to determine the factors behind the formation of clathrate-like water by means of molecular dynamics simulation. We find three factors; nano-confinement, hydrophobic environment and presence of suitably positioned anchoring groups govern the formation of clathrate-like water inside the protein. Nanoconfinement with hydrophobic environment produces nanoconfined ordered water which is further ordered and gets stabilized to form clathrate-like water through anchoring via hydrogen bonding by suitably positioned anchoring groups.

Materials and methods Molecular dynamics simulation All the molecular dynamics (MD) simulations and minimizations were carried out using GROMACS package118-120. OPLS-AA121-123 was used as a forcefield. We used TIP4P water model124,125. Reasons behind choosing OPLS-AA forcefield121-123 and TIP4P water model124,125 have been elaborately discussed in our previous study.80 MD equation of motions was integrated by Leap-frog algorithm with 2 fs time steps. Nonbonded cutoff was set to 1.0 nm. Particle Mess 6 ACS Paragon Plus Environment

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Ewald (PME)126 method was used for the calculation of long range electrostatic interactions with a grid spacing of 0.12 nm. Systems were minimized with steepest descent method. Most of the simulations were performed at 240 K and 1 atm pressure. 240 K temperature which is above the melting temperature of TIP4P water (232 K) is the active temperature for maxi protein in TIP4P water as discussed in our previous study80. Simulations of a total of around ten model systems were performed. For each system, we run backbone restrain molecular dynamics simulation for 20-30 ns for equilibration and 100-200 ns for production run at NPT ensemble using Nose-Hoover thermostat127,128 and Parinello-Rahaman barostat129. Analysis of water structure Structure of water was analyzed by calculating hydrogen bond angle distribution (O-O-H)79,117, O-O-O angle distributions79,130, conditional tetrahedrality (th)131, F3 order parameter34, four body (F4) order parameter38. For calculation of O-O-O angle, we have considered first coordination shell of the central water which is defined by O-O distance of 0.35 nm. Same O-O cut off (0.35 nm) was also used in the calculation of hydrogen bond angle (O-O-H). For each water pair, there are four possible O-O-H angles, minimum of which is taken in the calculation of hydrogen bond angle distribution. When O-O-O angle distribution provides the information about the tetrahedral ordering of water, strength of the hydrogen bond in water is known from hydrogen bond angle distribution. Consequence of O-O-O distribution is implicated in the calculated tetrahedral order parameter. As the majority of core water do not have four nearest neighbors, usual tetrahedral order parameter may not be able to provide good signal to noise in detecting water structural changes. We have therefore used conditional tetrahedral order parameter (th)131 in which the central water molecules can have 2 to 4 neighbors. th is given by, 1

𝑡ℎ𝑖 = 1 ― 𝑁(𝑁 ― 1)

( )∑ 9 8

1 2

(cos 𝜓𝑗𝑖𝑘 + )

𝑁―1 𝑁 ∑ 𝑗=1 𝑘=𝑗+1

3

with 2 ≤ N ≤ 4. 7 ACS Paragon Plus Environment

(1)


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Though the information about water ordering and strength of hydrogen bond can be known from hydrogen bond angle distribution (O-O-H)79,117, O-O-O angle distributions79,130, conditional tetrahedrality (th)131, they are not able to distinguish ice and clathrate. F334 based on O-O-O angle and F4 order parameter38 based on H-O--O-H torsion angle can differentiate between liquid, ice and clathrate. F3 order parameter measures the deviation from tetrahedrality and is given by, 𝑁―1 𝑁

2

𝐹3 = ∑𝑗 = 1 ∑𝑘 = 𝑗 + 1(|cos 𝜓𝑗𝑖𝑘|cos 𝜓𝑗𝑖𝑘 + 𝑐𝑜𝑠2(109.47𝑜))

(2)

Where N is the nearest neighbors within 0.35 nm from central water. It is usually used to detect ice and clathrate-like water.34-36,132-135 Average of liquid, ice and clathrate water are ~0.8, ~0 and ~0.1 respectively. Another order parameter, F4 38 which measures the H-O--O-H torsion angle between neighboring water molecules is defined as,

1 𝐹4 = 𝑛

𝑁

∑cos (3𝜑)(3)

𝑗=1

Where φ is H-O--O-H torsion angle in which hydrogen atoms are those which are furthest away from the oxygen atom of other molecule. F4 is routinely used parameter to distinguish between ice and clathrate.16,39,135-138 F4 of liquid, ice and clathrate water are ~0, ~-0.3 and ~0.7 respectively. Though F3 and F4 were developed for sI, they have been used for the characterization of other clathrate structures too.114,139 Results and discussion Presence of clathrate like-water inside the core of maxi protein: An appropriate model system to understand formation of clathrate-like water at ambient temperature and pressure


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Formation of Clathrate hydrate is a low temperature phenomenon. Because antifreeze proteins (AFP) and ice nucleating proteins (INP) functions at subzero environment, among the globular proteins only AFPs)39-44 and INPs42,46 produce clathrate-like water during their functioning. Many of the AFPs and INPs do not show preordering of water as much as to clathrate-like before ice recognition39-42,44. However, hyperactive type 1 AFP maxi protein shows clathrate-like water even in absence of ice surface as found in the crystal structure43. Therefore, a rigorous structural analysis of water is needed to verify the robustness of maxi to be used as a model protein to understand the formation of clathrate-like water. To analyze the water structure inside the first solvation shell (FSS) maxi, we first calculated hydrogen bond angle distribution (Figure 1B) and O-O-O angle distribution (Figure 1C). FSS is defined by a cut-off distance (~0.55 nm) which is the minima of the g (r) of oxygen atoms of water from the heavy atoms of protein. Distribution of hydrogen bond has two peaks. First peak represents the linear hydrogen bond and the second peak represents bent hydrogen bond. Enhancement of population of linear hydrogen bond and reduction of population of bent hydrogen bond indicates presence of stronger hydrogen bond. From Figure 1B, it is clear that water inside first solvation shell (FSS) of maxi protein forms more stronger hydrogen bond compared to bulk. O-O-O angle distribution (Figure 1C) also shows two peaks. Peak at ~60o is because of the presence of interstitial water molecules which are transient in nature. Peak at ~100o is measure of tetrahedral ordering. Increased population of O-O-O angle distribution at ~100o and decreased population of interstitial water (at ~60o) for FSS water of maxi clearly indicate that they are more tetrahedrally oriented than bulk water. Increased ordering of water is also implicated in the distribution of conditional tetrahedral order parameter (Figure 1D) as we found that there is shift and increment of peak towards higher value corresponding to better tetrahedral arrangement of 9 ACS Paragon Plus Environment


FSS water. To check extent of ordering we used two order parameters: three body F3 order parameter based on O-O-O angle and four body (F4) order parameter based on H-O--O-H torsion angle. These two order parameters are frequently used to identify ice-like and clathrate-like water. 16,34-36,39,132-138

F3 measures the deviation of tetrahedrality. For perfect tetrahedral arrangement, F3

is 0. F3 values of liquid water, ice and clathrate are 0.8, 0 and 0.1 respectively. Average is shown in Table-1 which clearly indicates that while bulk water is liquid like, there is signature of presence of partial clathrate-like water in the FSS water. Since nature of distribution of F3 of ice and clathrate are similar and the respective value are closed spaced, sometimes it becomes difficult to distinguish between ice and clathrate. Four body order parameter based on H-O--O-H torsion angle is quit robust to distinguish between ice and clathrate. In the calculation of F4, we measure H-O--O-H torsional angle of a water dimer and those hydrogens which are not involved in hydrogen bonding in the dimer are taken. Nature of the distribution of H-O--O-H torsional angle of ice, clathrate and liquid water are much different from each other. Liquid water has a flat distribution having no clear peak indicating random choice of angles. Distribution of angles in clathrate is bimodal: one peak at 0o and other one is at 120o which is slightly higher in population. In contrast, ice has a distribution with two dominant peaks at ~60o and at ~180o and two small peaks at ~0o and at ~120o. Looking at the distribution of torsion angles of ice and clathrate, the way to differentiate ice and clathrate visually is that maxima found at ~60o and ~180o in ice become minima in clathrate at those position. Distribution of H-O--O-H torsional angle of FSS water are shown in Figure 1E. Bulk water has distribution of angles which is ice-like whereas FSS water has a bimodal distribution with the two maxima of the distribution of angles of FSS water appearing at ~0o and 120o and the minima appearing at 60o and 180o. Therefore, the nature of distribution of H-O--O-H torsion angle of FSS water is somewhat like that of clathrate-like water. Using the


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values of H-O--O-H torsion angle, we calculated F4 order parameter for FSS water and bulk water and a framewise distribution of F4 is plotted in Figure 1F and Table-1. F4 of liquid, ice and clathrate is ~0, ~-0.3 and 0.7. F4 value of bulk water is ~-0.04 which indicates that bulk water is liquid-like whereas that of FSS water is 0.06 which hints presence of partial clathrate-like water.



Figure 1. Characterization of water structure inside the FSS of Maxi protein. (A) Unusual structure of Maxi protein in the context of hydrophobic core principle. (A1) Hydrated core of Maxi protein with lot of interior waters (red balls) and (A2) well-packed dry hydrophobic core (vdw representation in green color) of rop dimer. Structures in (A) were drawn in 12 ACS Paragon Plus Environment

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VMD140. Hydrogen bond angle distribution (B), O-O-O angle distribution (C) and conditional tetrahedrality (D) indicates presence of strongly hydrogen bonded ordered water inside the FSS of protein. Distribution of H-O--O-H (E) and F4 (F) hints presence of partial clathrate-like water. Unlike other globular protein, dimeric maxi protein has a hydrated core making maxi, a naturally occurring nano-pore. So, FSS of protein has two regions: one is inner core region and another is non-core FSS region.80 Though core water and non-core FSS water experience similar chemical environment, it still needs to be acquainted whether formation of clathrate-like water is observed in both regions or not as nano-confined water is different from bulk water. To elucidate this issue, we evaluated F3 (Table-1), distribution of H-O--O-H torsion angle (Figure 2A) and F4 (Figure 2B, Table-1) for core water and non-core FSS water. It is evident that F3 value of non-core FSS water (Table-1) is bulk-like whereas that of core water is clathrate-like. Distribution of H-O--O-H torsion angle (Figure 2A) also shows that distribution for non-core FSS water is flatter while the core water has clathrate-like distribution and population of peak at ~0o and ~120o is even increased when compared to FSS water. Consequence of H-O--O-H torsion is implicated in F4 also (Figure 2B, Table-1). F4 for core water is ~0.25 (Table-1). As the F4 of core water is not 0 (for liquid-like) and not 0.7 (for clathrate-like), they are termed as semi-clathrate water.



Figure 2. Structure of water in different region of maxi protein. (A) Distribution of H-O--OH torsion angle and (B) Distribution of F4 of FSS water (black), core water (red) and noncore FSS water (blue). When formation of clathrate-hydrate needs low temperature and moderately higher pressure, clathrate-like water is observed in biomolecular recognition of proteins such as AFPs, INPs at atmospheric pressure. So, it is important to determine the factors which govern the formation of clathrate-like water at atmospheric pressure. Because maxi shows clathrate-like water inside its core even in absence of ice surface, it will be a good model protein to understand the molecularlevel picture of formation of clathrate-like water at ambient pressure by looking at the structure of 14 ACS Paragon Plus Environment

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core water. Table-1: and of water in different region of protein Order parameter

Region Bulk water

FSS water

Core water

Non-core FSS water

0.63

0.50

0.25

0.56

-0.05

0.07

0.25

0.01

Effect of confinement on the formation of clathrate-like water inside the core of maxi Waters confined inside nanopores and cavities show unusual properties compared to bulk water.27,141-144 Four helix bundle structure with hydrated core makes maxi a naturally occurring nanopore. Therefore, it is important to check whether confinement made by maxi has any effect on the formation of clathrate-like water or not. Maxi is homo-dimeric protein. Monomer of maxi has double helical U-shaped structure and still has hydrated core (Figure 3A1). The degree of confinement for the core water in U-shaped monomer will be somewhat reduced when compared to dimer. As the monomeric unit is not very stable in water, we performed a simulation of monomer of protein by restraining the positions of its backbone heavy atoms. To check whether clathratelike water is still present inside the core of monomer or not, we calculated F3 (Table-2), H-O--OH torsion angle distribution (Figure 3A2) and F4 (Figure 3A3) of the core water of monomer and compared the values with that of homo-dimer. Though F3 value of core water of monomer is increased little bit from that of dimer, it is clearly not liquid-like, rather it indicates presence of 15 ACS Paragon Plus Environment


clathrate-like water inside the core of monomer. Distribution of H-O--O-H torsion angle (Figure 3A2) shows that though population of peak at ~0o and ~120o of core water of monomer is decreased from that of homo-dimer, nature of the distribution is still clathrate-like. F4 (Figure 3A3, Table-2) further confirms the presence of clathrate-like water inside the core of monomer. These results clearly indicate that though the degree of confinement is decreased in monomeric protein, clathrate-like water is still present inside the core of monomer. To reduce the confinement effect drastically, we cut the U-shaped monomer in the coil region in such a way that monomer splits into two halves (monomer-half1 and monomer-half2) which are long single helices (Figure 3B1). We simulated each half of the monomer by restraining the positions of heavy atoms of backbone. F3 (Table-2), H-O--O-H torsion angle distribution (Figure 3B2) and F4 (Figure 3B3) have been calculated in different size of solvation shell of each half of monomer. F3 values (Table-1) clearly indicate that water inside the FSS (0.55 nm from protein) of monomer-half1 (and also monomerhalf2, results not shown here) is liquid-like. The observed peaks at ~0o and ~120o in the H-O--OH torsion angle distribution of FSS (or core of monomer and homo-dimer) of maxi vanish in the monomer-half (Figure 3B2) and the distribution rather becomes flatter inferring liquid-like water. Suh liquid-like water is also implicated in the F4 distribution (Figure 3B3). These results conclude that confinement certainly plays a pivotal role in the formation of clathrate-like water inside the core of maxi protein at ambient pressure.


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Figure 3. Role of nano-confinement in the formation of clathrate-like water in Maxi. (A) and (B) show the results of monomer and monomer-half1 respectively. Cartoon representation of U-shaped monomeric protein (A1) and rod-like monomer-half1 (B1) with hydrophilic (red) and hydrophobic (cyan) sidechains (licorice representation) taken from VMD140. Ushaped monomeric protein (A1) with decreased confinement has clathrate-like water inside its core but with a reduction in population compared to homodimeric Maxi as evident from distribution of H-O--O-H (A2) and F4 (A3). Distribution of H-O--O-H (B2) and F4 (B3) of water inside different shell of monomer-half1 (B1) having no confinement further shows absence of clathrate-like water. Effect of sidechains on the formation of clathrate-like water inside the core of maxi 17 ACS Paragon Plus Environment


Next, we verify the effect of sidechain on the clathrate formation in the maxi protein. To this end, we mutated all residues of maxi to glycine to make a model protein of four helix bundle with hydrated core but without sidechain (Figure 4A). Mutation was performed in VMD140. For presentation purpose, we have named the mutated model protein as “All GLY”. Simulations of All GLY has been performed while keeping the backbone architecture same as maxi and evaluated F3 (Table-2), H-O--O-H torsion angle distribution (Figure 4B) and F4 (Figure 4C, Table-2) of the core water. It is evident from F3 value (Table-2) that core water of All GLY is liquid-like. Liquidlike water is further confirmed by H-O--O-H torsion angle distribution (Figure 4B) as we found a flatter distribution of core water of All GLY. F4 (Figure 4C, Table-2) also supports the presence of liquid-like water inside the core of All GLY. Though core water of All GLY is nanoconfined, it lacks sidechains. Presence of clathrate-like water inside the core of maxi having several sidechains and absence of clathrate-like water (or presence of liquid-like water) inside the core of All GLY having no sidechains clearly suggests that confinement is not the only factor; sidechains also have crucial role in formation of clathrate-like water. We have not observed clathrate-like water in the case of monomer-half of maxi which has sidechains but lacks confinement and also in the case of All GLY which has confinement but lacks sidechains. Therefore, it can be safely stated that a simultaneous presence of the effects of confinement and sidechains is necessary for the formation of clathrate-like water structure in the maxi protein.


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Figure 4. Role of sidechains on the formation of clathrate-like water inside the core of maxi. (A) is the VMD140 generated cartoon representation of model “All GLY” with no sidechains. Backbone is shown in licorice. Core water of “All GLY” (A) having nanoconfinement but no sidechains does not show signature of clathrate-like behavior in the distribution of H-O--OH (B) and F4 (C). Table 2: Comparison of and among bulk water, core water of Maxi and core water of “All GLY” model



Order

Bulk water

parameter

Core

water

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of Core water of Monomer-

homo-dimeric

monomeric

Maxi

Maxi

Core water of

half1

“All GLY”

F3

0.63

0.25

0.27

0.57

0.63

F4

-0.05

0.25

0.12

0

0

Effect of hydrophobic sidechains on the formation of clathrate-like water inside the core of maxi Results presented in the previous sections reveal a hint for the role of sidechains on the formation of clathrate-like water provided the confinement is present. In general, sidechains can be both hydrophilic and hydrophobic groups. Therefore, we explored whether only one group between the two promotes clathrate formation or both hydrophilic and hydrophobic groups are responsible. In general, clathrate-hydrates are composed of gas and water. Different types of water cages enclose the gas molecules. Methane, ethane, propane is analogous to hydrophobic sidechains of alanine, valine, leucine, isoleucine and they form gas hydrates. Therefore, sidechain of these hydrophobic residues may have some role in clathrate formation. To investigate the role of hydrophobic environment, we mutated all the hydrophobic residues of maxi into glycine by VMD140 and the mutated model is named as “Hydrophilic only”. In Hydrophilic only model, there is no hydrophobic sidechains, only hydrophilic sidechains are present and the model also has hydrated core intact to ensure the criteria of confinement (Figure 5A). We have performed a position restrain simulation of Hydrophilic only model by fixing the backbone. We have then calculated F3 (Table-3), H-O--O-H torsion angle distribution (Figure 5B) and F4 (Figure 5C, Table-


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3) of the core water. F3 and F4 value inside the core of Hydrophilic only model is liquid-like. Such liquid-like behavior is also reflected in the H-O--O-H torsion angle distribution (Figure 5B) which becomes flatter. It is observed that when hydrophobic environment is absent, we have not observed clathrate-like water though confinement and hydrophilic sidechains are present. So, presence of hydrophobic environment is another important factor behind formation of clathrate-like water.

Figure 5. Determination of role of hydrophobic sidechains in the formation of clathrate-like water through characterization of water in “Hydrophilic only” model having no hydrophobic environment in sidechain. (A) A VMD140 generated representative structure of the model “Hydrophilic only” having only hydrophilic sidechains (red, licorice). H-O--O-H 21 ACS Paragon Plus Environment


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torsion angle (B) and F4 (C) show absence of clathrate-like water inside the core of “Hydrophilic only” model. It indicates that clathrate-like water form in hydrophobic environment. Table 3: Comparison of and among bulk water, core water of Maxi and core water of “Hydrophilic only” model Order parameter

Bulk water

Core water of Maxi

Core

water

of

“Hydrophilic only” model F3

0.63

0.25

0.55

F4

-0.05

0.25

0

Effect of hydrophilic sidechains in the formation of clathrate-like water Next, we explore whether the presence of confinement and hydrophobic environment enough to produce clathrate-like water?. In our previous works79,80, we have found ordered water which are not clathrate-like water inside the core of solvent separated pair configurations of rod-like hydrophonbe79 and another hydrophobe resembling the shape of maxi80 even though both the hydrophobe pair fulfills the criteria of hydrophobic environment and confinement. However, Bai et al showed evidence of formation of guest-free monolayer clathrate within hydrophobic nanoslit but at low temperature which is much below the melting temperature of the water model (TIP5P)28 used in their simulations and also at moderately higher pressure.27 But, AFPs, INPs exhibits clathrate-like water at relatively ambient temperature and pressure.39-44,46 Maxi protein shows clathrate-like water above the melting temperature of water (232K for TIP4P water model). 22 ACS Paragon Plus Environment

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We even found glimpse of clathrate-like water at 300 K. The distribution of H-O--O-H torsion angle behaves similar to clathrate and the value of F4 of core water is higher than that of liquid water. We also found clathrate-like water at 275 K with TIP4P/Ice and TIP5P water model. Therefore, these results hint on the fact that apart from confinement and hydrophobic environment, there may exist other factors which also have role in clathrate-formation. To this end, role of hydrophilic sidechains has to be examined. Hydrophilic sidechains can make hydrogen bond with water. If the hydrogen bonding of water with sidechain anchors the clathrate formation, loss of the hydrogen bonding ability of hydrophilic sidechains should destroy the clathrate. To mute the hydrogen bonding ability of sidechain, we carefully made the partial charges of atoms of sidechain zero keeping total charge of the system neutral and partial charges of the atoms of backbone unaltered. It is easily doable in OPLS-AA forcefield as the charge distribution of backbone is independent from that of sidechain. For presentation purpose, model protein with zero partial charges of atoms of sidechains is named as “Hydrophobic sidechain” as all the sidechains in this model becomes hydrophobic (Figure 6A). To verify the effect of anchoring through hydrogen bonding of sidechains with water a simulation of Hydrophobic sidechain model was performed. Here also we calculated F3 (Table-4), H-O--O-H torsion angle (Figure 6B) and F4 (Figure 6C, Table-4). From F3 and F4 it is evident that clathrate like water observed inside the core of wildtype maxi still remains clathrate-like inside the core of Hydrophobic sidechain model. Rather we found similar F3 value and increased F4 value in the case of Hydrophobic sidechain model indicating formation of more clathrate like ordering of water compared to wildtype. Increased ordering of clathrate like water in Hydrophobic sidechain compared to wildtype is also reflected in H-O--O-H torsion angle distribution (Figure 6B) as there is enhancement of peaks at ~0o and at ~120o. If sidechain hydrophilic group had any role of anchoring through Hydrogen bonding with water in



clathrate formation, destruction of Hydrogen bonding ability of sidechains would reduce (or even destroy) the clathrate formation instead of facilitating clathrate formation. The results infer that sidechains Hydrophilic group has no significant effect on formation of clathrate like water.

Figure 6. Determination of role of hydrophilic sidechains in the formation of clathrate-like water through characterization of water in “Hydrophobic sidechain” model having no hydrogen bonding ability of sidechain. (A) A VMD140 generated representative structure of the model “Hydrophobic sidechain” with hydrophobic sidechains only (cyan, licorice). All the sidechains in this model become hydrophobic as the partial charges of the atoms of the hydrophilic sidechains have been made zero. H-O--O-H torsion angle (B) and F4 (C) show 24 ACS Paragon Plus Environment

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little increase in clathrate-like water inside the core of “Hydrophobic sidechain” model compared to that of Maxi denying anchoring role of hydrophilic sidechains through hydrogen bonding in the formation of clathrate-like water. Table 4: Comparison of and among bulk water, core water of Maxi and core water of “Hydrophobic sidechain” model Order parameter

Bulk water

Core water of Maxi

Core

water

of

“Hydrophobic sidechain” model F3

0.63

0.25

0.25

F4

-0.05

0.25

0.27

Role of backbone as an anchor in the formation of clathrate like water Like Hydrophilic sidechains, backbone can also make Hydrogen bond with water as the atoms of backbone have large partial charges and therefore can anchor the clathrate water. To verify backbone anchoring through hydrogen bonding with water, we carefully make the partial charges of atoms of backbone zero keeping total charge of the system zero and partial charges of the sidechains atoms untouched. And we named the model system as “Hydrophobic backbone” as the backbone in this model becomes hydrophobic (Figure 7A). We simulated Hydrophobic backbone model and calculated F3 (Table-5) and F4 (Figure 7C, Table-5), H-O--O-H torsion angle distribution (Figure 7B). F3 and F4 clearly show that the clathrate like water found inside the core of wildtype gets reduced in Hydrophobic backbone model. Ii is also evident from H-O--O-H torsion angle distribution that there is immense reduction of clathrate like water inside the core of 25 ACS Paragon Plus Environment


Hydrophobic backbone model. Clearly backbone has an anchoring role through Hydrogen bonding with water. In Figure 7D, we have shown backbone anchoring through hydrogen bonding with water.

Figure 7. Determination of role of backbone in the formation of clathrate-like water through characterization of water in “Hydrophobic backbone” model having no hydrogen bonding ability of backbone. A VMD140 generated representative structure of “Hydrophobic backbone” is shown in (A) where the hydrophobic backbone (cyan) is represented in licorice and sidechains (hydrophilic=red, hydrophobic=cyan) are represented in CPK. Backbone in 26 ACS Paragon Plus Environment

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this model is hydrophobic as the partial charges of the atoms of the backbone were made zero. H-O--O-H torsion angle (B) and F4 (C) show reduction in clathrate-like water inside the core of “Hydrophobic backbone” model (A) compared to that of Maxi indicating role of backbone in the formation of clathrate-like water. (D) Anchoring role of backbone through hydrogen bonding with water. Table 5: Comparison of and among bulk water, core water of Maxi and core water of “Hydrophobic backbone” model Order parameter

Bulk water

Core water of Maxi

Core

water

of

“Hydrophobic backbone” model F3

0.63

0.25

0.45

F4

-0.05

0.25

0.07

Confinement, Hydrophobic environment and anchoring through hydrogen bonding: Three factors behind formation of clathrate like water in bimolecular recognition at ambient temperature and pressure As discussed above, gas hydrate namely alkene-hydrates form at low temperature and high pressure. So, hydrophobic environment is the first thing to induce the formation of clathrate like water. Antifreeze protein (AFPs), ice nucleating protein (INPs) also show signature of clathrate like water during their biomolecular recognition. Because hydrophobic sidechains of this proteins (e.g. sidechain of alanine, valine, leucine, isoleucine) are analogues to the alkane of alkaneshydrate, it may not seem to be surprising to see clathrate like water during their biomolecular 27 ACS Paragon Plus Environment


recognition. But, if hydrophobic environment was the only inducing feature for formation of clathrate-like water, we would have found clathrate-like water in a majority of bimolecular structure. However, Clathrate-like water is observed in limited number of biomolecules. Also, when the process of formation of alkane-hydrate happens at low temperature and moderately higher pressure, formation of clathrate-like water in the context of biomolecular recognition of AFPs, INPs occurs at ambient temperature and pressure. So, there are other features along with presence of hydrophobic environment which conduce the formation of clathrate-like water. In our model system, maxi, we have shown that if the hydrophobic environment is removed, clathrate-like water vanishes. So, presence of hydrophobic environment is one of the factors. In the case of monomer-half, though hydrophobic sidechains are still present, clathrate-like water is not observed. The difference between monomer-half and monomer of protein (or the homo dimer) is that while the later has confinement, the former does not have it. So, confinement is another factor. In the present case, confinement is made by protein itself. In other cases, confinement may arise between protein and ice surface. However, in four helix bundle made up of all glycine residues (named as All GLY) no clathrate-like water is observed. In All GLY (and also in Hydrophilic only), though confinement is present but it lacks hydrophobic environment. So, there is a coupled role of hydrophobic environment and confinement. If one factor is absent, the other factor alone is not sufficient for clathrate formation as shown in Table 6. Apart from hydrophobic environment and confinement, there is also a role of backbone. Backbone has suitably positioned hydrogen-bonding groups which hold the clathrate-like water through hydrogen bonding and thus stabilize the clathrate-like water. When hydrogen bonding ability of backbone is destroyed by putting zero partial charges on the atoms of backbone, though signature of clathrate-like water is still present, there is huge reduction in clathrate-like order. In Table 6, we have shown that if 28 ACS Paragon Plus Environment

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confinement and hydrophobicity are present (indicated as black √ mark symbol) and anchoring is absent (indicated as Χ mark symbol), there is decreased clathrate-like water as indicated by single red √ mark symbol. So, confinement and hydrophobic environment forms ordered water. To stabilize those ordered water and eventually to make clathrate-like water, one needs perfectly positioned functional groups which can anchor those clathrate-like water via hydrogen bonding. In the present case, anchoring is via backbone. In other proteins sidechains may anchor the clathrate-like water. In Table 6, we have shown that if all three factors are present (indicated as black √ mark symbol), there is presence of clathrate-like water as indicated by double red √√ mark symbol. If the above discussed three factors are enough for formation of clathrate-like water, a model which fulfills those three factors may show clathrate-like water. To make such simple model with different chemical environment from wildtype maxi, we have mutated all the residues to alanine. The reason alanine has chosen is that it is the smallest amino acid with hydrophobic (methyl) sidechain. Mutated model has been named as “All ALA” (Figure 8A). Like maxi, All ALA is also a four-helix bundle with confined water inside the core. A simulation of All ALA was performed and consequently F3 (Table-7), F4 (Figure 8C, Table-7) and H-O--O-H torsion angle distribution (Figure 8B) were calculated. F3, F4 and H-O--O-H torsion angle distribution clearly shows that water inside the core is clathrate-like. To further confirm the anchoring role of backbone, we have again made the partial charges of backbone zero so that anchoring role of backbone is destroyed. We found that inability of backbone as an anchor reduces clathrate-like water as the value of F3, F4 move away from the original value and population at ~0o and ~120o in the distribution of H-O-O-H torsion angle is reduced. Table-6: Factors governing the formation of clathrate-like water at ambient temperature 29 ACS Paragon Plus Environment


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and pressure Hydrophobic

Confinement

Anchoring through H- Clathrate-like water

environment

bond

X

X

X

X

√

Χ

Χ

Χ

Χ

√

Χ

Χ

Χ

Χ

√

Χ

X

√

√

X

√

X

√

X

√

√

X

√

√

√

√

√√


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√ represents presence and X represents absence of factor. X represent absence, √ represents low clathrate-like water and √√ represents high clathrate-like water.

Figure 8. Characterization of water in “All ALA” model having three factors-confinement, hydrophobic environment and anchoring groups. (A) A VMD generated representative structure of “All ALA” with methyl sidechains (licorice, cyan color). Distribution of H-O-O-H torsion angle (B) and F4 (C) of core water of “All ALA” model is similar to that of Maxi that is core water of “All ALA” model is clathrate-like. Table 7: Comparison of and among bulk water, core water of Maxi and core water of “All ALA” model 31 ACS Paragon Plus Environment


Order parameter

Bulk water

Core water of Maxi

Page 32 of 49

Core water of “All ALA” model

F3

0.63

0.25

0.37

F4

-0.05

0.25

0.17

Conclusion In this study, we present a systematic approach to uncover the factors behind the observation of clathrate-like water in biomolecular structure by means of molecular dynamics simulation. While gas-hydrate usually forms at low temperature and high pressure, clathrate-like water in biomolecular structure is observed at ambient temperature and pressure. Though presence of hydrophobic environment is important, there are other factors play pivotal roles. We have observed that water confined inside the core of the model protein, maxi is clathrate-like. The clathrate-like water ordering vanishes when either hydrophobic environment or confinement is absent and they are found to be coupled. Along with hydrophobic environment and confinement, anchoring by the backbone through hydrogen bonding also plays important role to stabilize the clathrate-like water.


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AUTHOR INFORMATION Corresponding Author *Biman Jana *E-mail: [email protected]. Phone: +91 33 2473 4971. Notes

Authors declare no conflict of interest. ACKNOWLEDGMENT This research is supported by Department of Science and Technology SERB grant EMR/2016/001333 for funding. SP and BJ thank supercomputing facility CRAY at IACS for computational support. SP also thanks CSIR for awarding fellowships.

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