Progressive dry-core-wet-rim hydration trend in a nested-ring topology of protein binding interfaces
© Li et al; licensee BioMed Central Ltd. 2012
Received: 20 October 2011
Accepted: 27 March 2012
Published: 27 March 2012
Water is an integral part of protein complexes. It shapes protein binding sites by filling cavities and it bridges local contacts by hydrogen bonds. However, water molecules are usually not included in protein interface models in the past, and few distribution profiles of water molecules in protein binding interfaces are known.
In this work, we use a tripartite protein-water-protein interface model and a nested-ring atom re-organization method to detect hydration trends and patterns from an interface data set which involves immobilized interfacial water molecules. This data set consists of 206 obligate interfaces, 160 non-obligate interfaces, and 522 crystal packing contacts. The two types of biological interfaces are found to be drier than the crystal packing interfaces in our data, agreeable to a hydration pattern reported earlier although the previous definition of immobilized water is pure distance-based. The biological interfaces in our data set are also found to be subject to stronger water exclusion in their formation. To study the overall hydration trend in protein binding interfaces, atoms at the same burial level in each tripartite protein-water-protein interface are organized into a ring. The rings of an interface are then ordered with the core atoms placed at the middle of the structure to form a nested-ring topology. We find that water molecules on the rings of an interface are generally configured in a dry-core-wet-rim pattern with a progressive level-wise solvation towards to the rim of the interface. This solvation trend becomes even sharper when counterexamples are separated.
Immobilized water molecules are regularly organized in protein binding interfaces and they should be carefully considered in the studies of protein hydration mechanisms.
Water is an important component of biomolecules that is crucial to their formation and association , particularly in proteins folding  and binding . Many studies have been carried out, by energetic model/experiment or statistical analysis, to uncover the precise roles of water in protein-protein binding. It is widely understood that water molecules can shape the binding sites by filling cavities and can bridge local contacts by hydrogen bonds [4, 5]. Although its importance has long been recognized, water is usually excluded in protein binding interface modeling. An interface is often defined according to the change of the solvent accessibility of the residues before and after the binding [6, 7], or by the distance between the two chains in the complex [8, 9]. As these definitions do not involve water molecules, those residues that are in contact with the other chain indirectly through water molecules--e.g., wet spot residues [10, 11]--are missing in these interface models. The size of an interface is therefore underestimated. Actually, wet spots can account as much as 14.5% of the interface residues . As the missing residues are more likely to be in the interface than at the surface in terms of their mobility and energy contribution [10, 11], it is unreasonable to overlook interfacial water molecules even when the study is only focused on interfacial residues. Water molecules have also been ignored in most protein-protein interaction studies, especially those in computational approaches. For example, water is rarely considered in protein docking , interface analysis [6, 13, 14], interface classification [15–18], etc.
Few results are reported about the spatial arrangement of water molecules and their solvation trend in protein binding interfaces. An earlier work  pioneered the study of hydration patterns in protein interfaces, however, their patterns are isolated only within individual interfaces, which were not derived as a general trend. Their definition of interfacial water is prone of including many exposed water molecules. As some of their interfacial water molecules are actually not in interfaces at all, bias may be introduced to the analysis when the study steps to the fine solvation trend in protein interfaces.
Recently, we introduced a tripartite model of protein binding interfaces . Under this model, an interface is defined as an object of three compartments: the two binding sites of the two interacting chains and the interfacial water molecules. The interfacial water molecules are determined by a recursive computational method. As this newly proposed protein binding interface model is different from traditional definitions of protein binding interface, we named it a protein-water-protein interface, or a tripartite interface. A protein-water-protein interface can be represented by a tripartite graph, in which the nodes represent the residues or atoms, depending on the level of the study, and the edges are the contacts among them.
In this work, we conduct a topological analysis of water molecules in protein-water-protein interfaces. The distribution profiles of water molecules in three types of interfaces: obligate interfaces, non-obligate interfaces, and crystal packing contacts are investigated. In the analysis, a feature of atoms and residues, called burial level, is sophisticatedly explored. Burial level is defined with respect to an atomic contact network of a protein complex, describing the extent an atom or residue is buried in the protein complex. The atoms of an interface are then organized as a nested-ring topology where atoms at the same burial level in the interface are grouped into level-wise rings. We examine both overall and level-wise views of water arrangements in the interface and on the rings. We find that the interior of protein binding interfaces is not homogeneously the same everywhere in terms of a variety of properties such as wetness, water detectablity, polarity and mobility. Moreover, water molecules in protein binding interfaces are distributed in a dry-core-wet-rim style, suggesting that the solvation of protein interfaces occurs progressively ring-by-ring from core to rim in protein binding interfaces. It is also found that the function of an interaction seems to be another constraint of the associated water arrangement. All of these results indicate that water is an active player in protein binding interfaces and should be considered in the studies of protein binding interfaces.
Detectability of water molecules at different burial levels of protein interfaces
The amount of water molecules (in a protein complex) that can be detected by X-ray crystallography is closely correlated with the resolution at which the crystal structure is solved . A previous work also found that the quality of interfacial water information is subject to the resolution of the crystal structure . We investigated correlations between the wetness and resolution of crystal structures of protein interfaces. The average correlation coefficients between the wetness of an interface and the resolution (the resolution value) of the crystal structures of the obligate, non-obligate and crystal packing interfaces in our data are negative, being -0.4015, -0.5460 and -0.5632 respectively. This indicates that water-related properties of protein interface depend on the detectability of the water molecules. This observation is consistent with previous results reported by Rodier et al..
Wetness of different types of interfaces
Summary of water related properties of interfaces.
No. of interfaces
avg. No. of atoms
610.6 ± 354.2
318.0 ± 131.7
482.7 ± 314.9
186.0 ± 91.8
308.3 ± 259.1
avg. No. of water
28.68 ± 24.03
12.95 ± 9.72
21.80 ± 20.65
10.13 ± 8.46
14.94 ± 15.83
0.044 ± 0.023
0.039 ± 0.021
0.042 ± 0.022
0.053 ± 0.031
0.049 ± 0.029
1.577 ± 0.391
1.414 ± 0.281
1.506 ± 0.356
1.282 ± 0.267
1.374 ± 0.326
0.366 ± 0.026
0.385 ± 0.027
0.374 ± 0.028
0.398 ± 0.038
0.388 ± 0.036
1.052 ± 0.172
1.084 ± 0.169
1.066 ± 0.171
1.134 ± 0.196
1.106 ± 0.189
4.815 ± 1.547
3.960 ± 0.777
4.442 ± 1.337
3.354 ± 0.557
3.803 ± 1.098
Difference between types of interfaces.
OB vs. NO
4.2730 × 10-10
BIO vs. CP
2.3446 × 10-7
2.4387 × 10-25
2.6622 × 10-5
Level-wise distribution of water in protein interfaces
Given a tripartite interface, we partition its atoms according to their burial levels. Atoms at the same burial level are organized as a ring. The ring of "core atoms" consists of those atoms with the highest burial level in the interface. The rings are then ordered with the ring of core atoms in the middle. Thus, a tripartite interface can be viewed as a nested-ring structure. The ring of core atoms is denoted by O0, the ring closest to the core is denoted by O1, similarly for O2, etc. We examine how water molecules are distributed in these rings of an interface by looking at level-wise wetness. As the highest burial level varies a lot from one interface to another, we choose the core of interfaces as the starting point to see the change trend of level-wise wetness towards to the rim of the interfaces.
Level-wise property of interfaces.
Recall that the (negative) correlation between wetness and crystal structure resolution is stronger when the burial level becomes shallower. Thus the wetness of the outer rims of interfaces is more likely to be underestimated than that of the cores. This means that the increase in wetness from core to rim is affirmatively reliable in spite of the different water information quality at different burial levels.
To better understand the influence of water information quality unevenness, we divided the interfaces into three groups according to their level-wise wetness trend: strictly dry-core-wet-rim interfaces, strictly wet-core-dry-rim interfaces, and other interfaces. Strictly dry-core-wet-rim interfaces are referred to as those interfaces whose level-wise wetness increases monotonically from core to rim, while strictly wet-core-dry-rim interfaces are those interfaces whose level-wise wetness decreases monotonically from core to rim. We found, as expected, strictly dry-core-wet-rim interfaces are much more abundant than strictly wet-core-dry-rim interfaces. Over the obligate, non-obligate, and crystal packing interfaces in the data set, there are 87, 83, and 342 strictly dry-core-wet-rim interfaces but only 17, 26, and 124 strictly wet-core-dry-rim interfaces respectively. The strictly wet-core-dry-rim interfaces suffer more from the bad resolution and hence from the bad water information quality. The average resolution for strictly dry-core-wet-rim obligate, non-obligate and crystal packing interfaces are 1.98 Å, 2.18 Å and 2.11 Å, respectively, while the average resolution for strictly wet-core-dry-rim obligate, non-obligate and crystal packing interfaces are 2.35 Å, 2.29 Å and 2.16 Å, respectively (p-values of one-sided difference test: 0.0015, 0.1037 and 0.0403, respectively). This indicates that some water molecules in the rim of the interfaces are not reported and hence the actual wetness of these rims are underestimated, resulting in an overestimate of the number of strictly wet-core-dry-rim interfaces. Nevertheless, there are some high resolution strictly wet-core-dry-rim interfaces. In our data set, there are 4 obligate and 5 non-obligate interfaces that are strictly wet-core-dry-rim interfaces with a resolution better than 2.0 Å. As they are not abundant, we refer them as counterexamples to the dry-core-wet-rim hydration pattern.
Three examples of dry-core-wet-rim interfacial water topological arrangements are presented in Figures 7(b), (c) and 7(d). In the DTDP-glucose 4,6-dehydratase dimer interface shown in Figure 7(b), a large desolvated interface core is observed with rings of gradually increasing water molecules distributed towards to the rim of the interface. In another obligate interface in the aspartate aminotransferase shown in Figure 7(c), more water molecules are observed than in the first example, and several of them penetrate into the core of the interface; yet the amount is not as abundant as that observed in the rim. A twisted non-obligate interface between eEF1A and eEF1Balpha is shown in Figure 7(d). It also shows a dry-core-wet-rim water topology, with a higher wetness than the first two examples. In these three cases, their level-wise wetness goes up progressively from core to rim, being strictly dry-core-wet-rim interfaces.
Function and interfacial water arrangement
Interfacial water enrichment and organization are different in different functional groups of interfaces. We have manually examined the non-obligate interactions in our data set. Here we describe three types of them, enzyme-inhibitor interactions antibody-antigen interactions, and interactions containing shared hub proteins.
Difference between protease-inhibitor and other enzyme-inhibitor interfaces.
No. of interfaces
Inhibitors usually bind to the active site of an enzyme to block the access to its substrate. Proteases are enzymes that are capable of hydrolyzing peptide bonds. As most inhibitors of proteases are proteins, one mechanism for an inhibitor to avoid being hydrolyzed by the binding protease is to achieve a tight binding between the inhibitor and the enzyme so that water, which is needed in the hydrolysis reaction, is blocked from reaching the active site [27, 28]. Thus it is functionally important that the water molecules are excluded from the active site in protease-inhibitor interfaces, resulting in their low wetness. Moreover, the active site is usually located at the center of an interface; thus preventing water from accessing it generally reduces the burial level of water molecules and hence reduces the rWBL, making protease-inhibitor interfaces perfect dry-core-wet-rim interfaces.
There are 10 antibody-antigen interfaces in the data set. They are very wet with an average wetness 0.047. If only crystal structures of resolution better than 2.0 Å are considered, the average wetness becomes 0.064. Their average rWBL is only 1.037, lower than the average rWBL of all the non-obligate interfaces in the data set. The major difference between antibody-antigen interactions and other non-obligate interactions is that antibody and antigen are poorly related in evolution yet their binding is still of very high affinity and specificity.
This extraordinary requirement for both high binding affinity and specificity has resulted in a specific water distribution topology in antibody-antigen interfaces. Polar and charged residues are often used in antibody-antigen interfaces to enhance the binding specificity. These residues are capable of forming hydrogen bonds and salt bridges; and the electrostatic distribution on antigen and antibody binding sites can selectively determine to which they will bind . This leads to a high hydrophilicity at the interface. In order to achieve high binding affinity at the same time, the hydrogen bonds and salt bridges are usually networked through interfacial water molecules [31, 32], which in turn elevates the wetness of the interface.
Interfaces involving hub proteins
Some proteins can interact with many different partners, and maintaining many different functions. These proteins are typically called "hub" proteins. We investigated the water distribution topology of hub proteins by using the "shared proteins" proposed by Keskin and Nussinov . Similar binding sites of these shared proteins are observed to bind with different partners. In protein-protein interaction networks, these proteins are of large connectivity. In terms of structure, these interfaces are of smaller size with larger gap between the two partners, and their shape is flatter.
In our non-obligate interface data set, 10 are also reported in  as this kind of interface (Type 3 as in ). The average wetness of them is 0.036, insignificantly lower than the overall wetness of non-obligate interfaces, which is, however, unexpected as interfaces containing shared proteins are believed to have more water molecules to bridge inter-protein contacts . Moreover, their rWBL is very low (mean: 0.992), significantly lower than other non-obligate interfaces (p-value: 0.021, one-sided Mann-Whitney U test). It seems that water exclusion is very important for them.
It is widely known that exposed protein surfaces directly accessible to bulk solvent are dramatically different from the interiors of protein interfaces . We also find that the interior of protein interface is not the same everywhere in terms of wetness, water-detectability or polarity. Among the reasons for this unevenness, the distance to the bulk solvent--i.e. burial level--is an important one. As discussed earlier, if the interface is organized into rings of residues from its core to the rim, the properties of the rings are different. This reminds us of the famous "O-ring" theory [38, 39]. The "O-ring" theory suggests that there is a cluster of residues residing at the core of an interface, contributing most to the binding free energy, while other interfacial residues surround them in a ring-like manner to protect them from the bulk solvent. Our results suggest that there are indeed nested rings of residues in a protein binding interface, progressively growing from the center to the rim of the interface, showing a level-wise pattern. Moreover, the core of an interface is sheltered from water molecules by several rings of atoms, the desolvation power of which increases when one gets deeper into the interface.
The role of water molecules may also be different in different levels of the interface. One of the most important roles of water in protein binding interfaces is bridging the inter-protein contacts by hydrogen bonding with both sides. Specifically, interfacial water molecules prefer to make donor-water-donor or acceptor-water-acceptor hydrogen bond bridges, where the two groups are not complementary to each other originally . We investigated the hydrogen bonds formed by interfacial water molecules at different burial levels (using HBPLUS ). The percentage of non-complementary interface hydrogen bond bridges at different burial level is shown in Figure S1 (see Additional file 1). Although fluctuation is observed for transient interfaces, for obligate and crystal packing interfaces, it is observed that deeply buried water molecules are more likely to mediate non-complementary hydrogen bonds.
These observations suggest that protein interfaces do not simply follow a hot spot/O-ring dichotomy. Rather, a protein binding interface is subject to a progressive change in the physicochemical properties from core to rim.
According to the "O-ring" theory, the energy contribution of hot spots in the core is much stronger than the outer ring in the rim. We believe that the energy importance is growing progressively from rim to core, ring by ring. A direct correlation between the energy and burial level can be seen from the Generalized Born model  of solvation free energy, in which the atoms are characterized with an effective Born radius. Similar to burial level, the effective Born radius of an atom generally reflects how deep the atom is buried in the solute. However, it is set as a constant in practice. The electrostatic energies also seem to be related to burial level, as the dielectric constant of water is different from that of protein interior. The dielectric constant of water is around 80 , while the dielectric constant of protein interior is roughly in the range between 1 and 20 . In energy functions, this difference is considered in a very rough manner, previously. For example, in the FoldX energy function , the dielectric constant is linearly scaled from 8 to 80, according to the volumes of the nearby atoms within a distance of 6 Å. There is no further differentiation when atoms are more than 6 Å underneath the surface.
In our previous work , we proposed a hot spot prediction model based on the burial level of residues. We found that the average burial level of the atoms in a residue has a positive correlation with the ΔΔG caused by alanine mutation with a coefficient of 0.4588. Thus, we believe that incorporating burial level to energy functions explicitly or implicitly will increase the accuracy of binding free energy and hot spot prediction.
We also note that the water distribution topology is different between obligate and non-obligate interfaces, and also between biological and crystal packing interfaces. This encourages us to perform interface classification by taking interfacial water into consideration. For other applications, for example, protein docking, adding water into the model has been already proved to be useful . The general dry-core-wet-rim distribution topology may also be considered in this kind of application to understand a modeled binding interface, or a real binding interface.
We have studied level-wise water distribution profiles of protein interfaces using a tripartite graph model of protein binding interfaces, i.e., protein-water-protein interfaces. The water arrangement in biological interfaces can be distinguished from that in crystal packing interfaces in different ways such as higher wetness and lower relative water burial level. Differences between obligate and non-obligate interfaces are also observed, yet they are not as significant as those between biological and crystal packing interfaces. Water molecules are generally organized in a dry-core-wet-rim hydration pattern in an interface, suggesting that the core of an interface is protected incrementally by rings of progressively desolvated atoms. We have also conducted an analysis on the water arrangements in different functional groups of protein interfaces. It turns out that the water distributions are subject to the function of the interfaces.
Our set of obligate and non-obligate interactions are taken from a few previous works. The obligate interactions include those obligate interactions used by Mintseris and Weng  and Zhu et al., as well as those homodimeric proteins used by Ponstingl et al. and Bahadur et al.. Our non-obligate interactions include those protein complexes used by Bahadur et al., transient interactions used by Mintseris and Weng  and non-obligate interactions used by Zhu et al.. Crystal packing interactions are collected from the Protein Data Bank (PDB)  by taking those interfaces between two chains that are from different biological assemblies according to "REMARK 350". For a protein complex, if another version of the PDB entry with a better resolution (a smaller resolution value) is available, only the better one is used in this work. Redundancy is removed by using a sequence similarity threshold of 30%. That is, if the sequence similarities of any two chains, each from one side of the interaction, with a chain pair from another interaction are both larger than 30%, one of the interfaces is removed. To guarantee the quality of water information, interfaces whose PDB structure contains less than 20 reported water molecules or whose oxygen atoms of water are less than 1% of all the heavy atoms are eliminated. If any chain of an interface requires coordinate transformation, the corresponding interface is removed. Interfaces with less than 100 heavy atoms or have no interfacial water molecules are also eliminated. We removed interfaces with no water--there are only a few such cases--is the reason that it is hard to define the water burial level (WBL, defined later) of such interfaces.
This process results in a total of 206 obligate interactions, 160 non-obligate interactions and 522 crystal packing interactions in our data set. Complete lists of these interfaces are available in Tables S1-S3 (see Additional file 1). It should be noted that the "REMARK 350" in a PDB header is not always correct. However, we believe that such cases are not abundant in this relatively large data set [48, 49]. The conclusions we make are hence reliable.
Construction of atomic contact graphs and protein-water-protein interfaces
We distinguish immobilized water molecules and exposed water molecules in a protein complex by an iterative procedure. First, the solvent accessible surface area (SASA) of the atoms is calculated. Water molecules with SASA larger than 10 Å2 are removed. Then SASAs are calculated again based on the updated structure. This procedure is repeated until there is no water molecule with SASA larger than 10 Å2 in the structure. We refer to the removed water molecules as exposed water molecules and those remaining in the structure as immobilized or buried water molecules.
An atomic contact graph is built based on the structure resulting from the removal of exposed water molecules. The nodes of the graph are atoms and the edges are contacts between atoms. Two atoms are defined to be in contact if (i) they share a Voronoi facet and (ii) their distance is less than their radius plus 2.75 Å, which is the diameter of a water molecule. Two residues are defined to be in contact if there is at least one pair of atoms, one from each residue, that are in contact. The nodes in the atomic contact graph are labeled as "exposed" or "buried" based on their SASA with a threshold of 10 Å2. A pseudo node that represents the bulk solvent is added into the graph; this node is directly connected to all the exposed atoms.
We use V IA and V IB to denote the interfacial atoms/residues from chain A and B respectively. Our model of protein interfaces can capture those water molecules that immediately bridging the two parts, i.e. water molecules that forming protein-water-protein contacts. That's why we name interfaces under our model protein-water-protein interfaces. We do not consider higher order interfacial water bridges, such as protein-water-water-protein contacts. We believe they are less important and less abundant. More details about the Voronoi facets and the initial idea of the tripartite model of protein binding interfaces can be found in our earlier work .
Calculation of wetness
Suppose O is a protein-water-protein interface, we denote its atom-level tripartite graph as
O = < V IA (O) ∪ V IB (O) ∪ V IW (O), C I (O) >, where V IW is the set of oxygen atoms of interfacial water molecules.
where |X| is the cardinality of set X.
The size of an interface O is the number of interfacial atoms, including atoms of the amino acids from both sides and the oxygen atoms in the interfacial water molecules, namely |V IA (O) ∪ V IB (O) ∪ V IW (O)|.
We also define the overall polarity as well as the level-wise polarity of an interface as the proportion of polar atoms, counting O, N and S atoms as polar atoms.
The planarity of an interface is defined as root mean square deviation of non-water interfacial atoms from the least-squares plane of them .
Here, is the mean of X and n is the sample size.
publ This work was funded in part by two Singapore MOE Tier-2 grants (T208B2203 and MOE2009-T2-2-004). Part of the research by JL was conducted at NUS under a visiting fellowship.
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