Water dynamics at the binding interface of four different HLA-A2peptide complexes
Wilson S. Meng1,
Hermann von Grafenstein2 and
Ian S. Haworth
Department of Pharmaceutical Sciences, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089-9121, USA
Correspondence to:
I. S. Haworth
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Abstract
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Because only a limited number of MHC molecules are available for presentation of a large number of peptides, each of these MHC molecules must be able to bind promiscuously many different peptides at an affinity sufficient for stable presentation. Here we show, for the MHC molecule HLA-A2, that this ability may be facilitated by a flexible water network that forms an interface between the MHC molecule and the peptide. Using the SURFNET program we have computed the `gaps' present in the peptide-binding groove in the X-ray structures of complexes of HLA-A2 with four different bound peptides. The volume of these gaps increases with increasing peptide hydrophilicity. Using molecular dynamics simulations, we show that the water molecules in the binding groove of complexes of HLA-A2 with the more hydrophilic peptides are largely disordered, but a number of defined water-binding sites are also discernable. Conversely, for complexes of HLA-A2 with the more hydrophobic peptides, the water molecules are more rigidly bound at the MHCpeptide interface and a number of well-defined water-binding sites exist. However, even these well-defined sites may not be permanently occupied by the same water molecule and in the dynamics calculations we observed exchange of water molecules between such sites.
Keywords: MHC, molecular dynamics, peptide, water mediated
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Introduction
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Class I MHC molecules are cell-surface proteins that present peptides derived from intracellular proteins to cytotoxic T cells. This presentation process plays a crucial role in the immune response against infections with intracellular pathogens and tumors (1). In humans, each individual can express up to six different class I MHC molecules that are responsible for presenting peptides from a large variety of potential pathogens. Therefore, any given MHC molecule must be able to bind many different peptides. This `promiscuity' has been shown for many class I MHC molecules including the human leukocyte antigen HLA-A2, a common human class I allele (2,3). MHCpeptide interactions can occur in the nanomolar range of peptide concentrations (4) and such degeneracy of binding specificity is unusual for a ligandreceptor interaction of this affinity. Conversely, it has been shown that MHC molecules can discriminate between minor differences in peptide amino acid sequence (5,6). In this context, much effort has been directed towards trying to predict which peptides bind to a given MHC molecule (for a recent review, see 7).
Class I MHC molecules have two membrane-proximal Ig-like domains and a membrane-distal peptide-binding groove formed by an eight-stranded ß-sheet and two
-helical regions (8). X-ray structures of MHCpeptide complexes suggest that most class I MHC-bound peptides adopt similar backbone conformations (for reviews, see 9,10, and, for examples, see 1120). The peptide C- and N-termini are buried deep within the binding groove, and are important in the overall energetics of the peptideMHC interaction (21,22).
A large number of other direct contacts occur between the peptide and the MHC molecule. However, there is also considerable void space observable at the MHCpeptide interface in X-ray structures of the human class I MHC molecule HLA-A2 complexed with different peptides. This apparent space may be filled by water and we have shown in previous molecular dynamics simulations that ~11 water molecules are necessary to stabilize the X-ray conformation of the peptide GILGFVFTL in its complex with HLA-A2 (23). These water molecules exchange between different sites in the binding groove and form a flexible hydrogen bond network involving both the protein and the peptide (23).
Here we provide an analysis of the water-filled space in the binding groove of HLA-A2 complexes with four nonamer peptides. We show that the volume of this space is related to the relative hydrophobicity of the peptide. This volume is larger in HLA-A2 complexes of more hydrophilic peptides and hence more water molecules occupy the groove of such complexes. Based on molecular dynamics simulations, we then show that well-defined binding sites for water molecules occur in all the complexes, but to a greater extent in the complexes of HLA-A2 with the more hydrophobic peptides. Further, although the sites themselves are well-defined, over the course of the simulation they are not all occupied by the same water molecule and exchange of water molecules between sites was observed. We propose that the flexible nature of the water network in the binding groove allows the MHC molecule to present an array of binding surfaces that can accommodate many peptide sequences.
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Methods
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Structural analyses were performed using the molecular modeling package Quanta (Molecular Simulation, San Diego, CA) version 4.0 on a Silicon Graphics Indigo2 workstation. Molecular graphics representations of the results were produced using the same package. X-ray structures of HLA-A2 with four peptides (Table 1
) were retrieved from the Brookhaven Protein Databank (PDB entries: 1HHG, 1HHJ, 1HHI and 1HHK).
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Table 1. Properties of peptides and a summary of results from molecular dynamics simulations of HLA-A2peptide complexes
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Gaps between the peptide and the MHC molecule were located using the program SURFNET (24). A minimum sphere radius of 1 Å and a maximum sphere radius of 3 Å were used in the calculations as recommended by the author of the algorithm (24,25).
The solvent-accessible surface of each complex was calculated using the Connolly algorithm (26) with a probe radius 1.4 Å. In this calculation, the peptide and the MHC molecule were considered as one entity and a single surface was generated. This then allowed the SURFNET-derived gaps for each complex to be distinguished based on whether they were in contact with the solvent-accessible surface.
To compare the different complexes, we introduced a quantitative representation of the gaps calculated using SURFNET for each complex. We refer to this as the gap index (GI). This relates the volume and location of a gap to the C
atom of four amino acids of the MHC molecule (Y27, Y7, R97 and K121) that are located in the ß-sheet of the binding groove and define the region in which peptides bind (see schematic in Fig. 2
).

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Fig. 2. GI profiles for four HLA-A2peptide complexes: (a) 1HHG, (b) 1HHJ, (c) 1HHI and (d) 1HHK. Gaps are related to the C positions of four HLA-A2 amino acids that define the floor of the peptide-binding groove (Y27, Y7, R97 and K121).
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For each C
atom of Y27, Y7, R97 and K121, the GI is calculated by the equation:
where Vi (Å3) is the volume of the gap (i) calculated from SURFNET and di (Å) is the distance between the C
atom of an HLA-A2 amino acid and the grid center of gap (i). Only gaps within 12 Å of the C
atom were considered. Due to the dependence on di2, gaps centered between the floor of the binding groove and the peptide have a higher GI than those that are closer to the bulk solvent. This serves to filter out gaps that are created by solvent-exposed side chains of the protein and the peptide. The GI calculated for the C
atoms of Y27, Y7, R97 and K121 in each complex were then combined to generate a profile of SURFNET-calculated gaps for each complex.
Fully solvated 400 ps molecular dynamics simulations were also performed using AMBER 4.0 (27). The starting conformations for the dynamics simulations were the X-ray crystal structures of the HLA-A2peptide complexes. Each structure was solvated in the following way. First, the peptide was removed from the binding groove and the empty HLA-A2 molecule was solvated with a 25 Å radius TIP3P water sphere (28) centered upon the center of mass of the MHC molecule. In the absence of the peptide, this resulted in the binding groove being filled with water molecules. Following superimposition of the peptide (in its crystal structure location) on the groove water molecules, the solvent was minimized for 2000 steps, followed by 5 ps of molecular dynamics and a further 2000 steps of minimization to relieve peptidewater clashes. This solvent shell was then fully equilibrated using a further 50 ps of molecular dynamics and a third 2000 steps of minimization. In this pre-equilibration phase, the structure of the MHCpeptide complex was fixed.
The protocol for the simulation of the fully solvated HLA-A2peptide complexes has previously been described (23). Briefly, the solvent-equilibrated structure was minimized for 2000 steps followed by a 400 ps molecular dynamics simulation, including an initial heating phase from 0 to 298 K in 10 ps, using time steps of 2 fs. Coordinates were saved every 0.4 ps. Water molecules that occupied the peptide-binding groove at any point in the dynamics trajectory were identified using in-house software written specifically for this purpose.
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Results
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The sequences of the four peptides used in this study are listed in Table 1
. Crystal structures of these peptides in complex with HLA-A2 are available (15). An inverse correlation between increasing hydrophobicity of the peptide and the volume of the water-filled space in the binding groove was observed based on calculations using a program that allows gaps in proteins structures to be determined (SURFNET) (24) and the calculated GI (see Methods). In the following sections, we present a visualization of the SURFNET gaps, based on their accessibility to bulk solvent, and quantify the volume and location of the gaps. We then use molecular dynamics simulations to obtain a description of the structure and dynamics of the water molecules that fill the gaps.
A representation of the gaps calculated using SURFNET for each MHCpeptide complex is shown in Fig. 1
. The gaps are colored in blue if they are in contact with the solvent-accessible surface of the complex and in yellow if they are `isolated' from the bulk solvent. For the complex with the most hydrophilic peptide (1HHG, Table 1
and Fig. 1a
) only a solvent-accessible gap is present, whereas in complexes with the more hydrophobic peptides (1HHI and 1HHK, Table 1
, Fig. 1c and d
), only gaps that are isolated from the bulk solvent are seen. For a complex with intermediate hydrophilicity, both types of gaps are found. The largest gap in 1HHG (Fig. 1a
) is a channel connecting the interior of the binding groove to the bulk solvent.

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Fig. 1. A comparison of the SURFNET-calculated gaps for four HLA-A2peptide complexes: (a) 1HHG, (b) 1HHJ, (c) 1HHI and (d) 1HHK. Each complex is viewed such that the N-terminus of the peptide is on the left. The peptide is colored in green and the MHC molecule is colored in white. Gaps that make contact with the solvent-accessible surface are colored in blue and those that do not are colored in yellow.
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In Fig. 2
, the distribution of the gaps in the peptide-binding groove is quantified for each complex, based on the calculation of the GI (see Methods). A common feature of each complex is the small gap close to the N-terminus of the peptide, defined by Y27 (Fig. 2ad
). In the X-ray structure of HLA-A2 alone (without a peptide) (29) and in several X-ray structures of other MHCpeptide complexes (13,17,30,31), a bound water molecule has been observed in a similar position close to the N-terminus. Larger gaps are seen in the vicinity of Y7 or R97. Based on our earlier simulations of the HLA-A2GILGFVFTL complex (1HHI), it is likely that this `void volume' in the MHCpeptide complexes is filled with water molecules (23), and we have examined this using molecular dynamics simulations.
We performed 400 ps molecular dynamics simulations of each complex. Prior to analyzing the details of the dynamics of the water in each complex, we established that the X-ray conformation of the peptide was retained over the course of the trajectory. The average root mean square deviations of the peptides over the simulation trajectories were all <1.7 Å. At no point in the trajectory was a peptide conformation observed that had a root mean square deviation >2 Å, which is well within the 2.6 Å resolution of the X-ray structures (15). The overall conformation (as assessed by monitoring the
,
and
angles) of each peptide remained essentially unchanged over the course of the simulation.
Table 1
shows a summary of the number of water molecules inside the binding groove of each complex in the molecular dynamics simulation. Although at any given time point more water molecules occupied the groove in the complexes of the hydrophilic peptides (1HHG and 1HHJ), a smaller percentage of these remained in the groove for the duration of the simulation (Table 1
). Hence, more exchange occurred between the bulk solvent and the binding groove in the complexes of the hydrophilic peptides, consistent with the nature of the SURFNET-derived gaps. For the hydrophobic peptides (1HHI and 1HHK) the calculated gaps appear to be isolated from solvent (Fig. 1c and d
) as determined by SURFNET, but it is apparent in the dynamics simulations that limited exchange of water molecules between the groove and the bulk solvent can still occur.
We have previously suggested that water molecules in the binding groove of 1HHI occupy specific sites, but that exchange occurs amongst these sites (23). To illustrate and compare this property for the four HLA-A2peptide complexes, we show in Fig. 3
the groove water network for each complex, using the position of the water oxygen atom to define the location of the water molecule, and superimposing structures taken at 0.4 ps intervals from a 400 ps dynamics simulation. Hence each network shown in Fig. 3
comprises 1000 separate structures.


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Fig. 3. A representation of the groove water networks in four HLA-A2peptide complexes: (a) and (a') 1HHG, (b) and (b') 1HHJ, (c) and (c') 1HHI, and (d) and (d') 1HHK. The water network in each complex comprises 1000 structures taken at 0.4 ps intervals in the molecular dynamics simulation and is shown using two color schemes. On the left, the water molecules are colored based on the adjacency to amino acids R97 (blue), D77 (red) and Y99 (white) of the MHC molecule, and amino acids at positions 5 (yellow) and 7 (green) of the peptide. On the right, the identical groove water network is represented with each individual water shown in a different color (see text).
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The water networks (Fig. 3
) are represented using two different color schemes. The first of these (Fig. 3a, b, c and d
for 1HHG, 1HHJ, 1HHI and 1HHK respectively) shows water molecules colored based on their adjacency to key amino acids of the MHC molecule or the peptide. These are water molecules close to the side chains of R97 (blue water molecules), D77 (red) and Y99 (white), and the carbonyl oxygen atoms of amino acids at position 5 (p5, yellow) and 7 (p7, green) of the peptide. This color scheme shows clustering of water molecules into specific sites defined by interactions with the peptide and the protein. Some of these clusters are diffuse and this is particularly true for the hydrophilic peptides (Fig. 3a and b
). The second color scheme (Fig. 3a', b', c' and d'
for 1HHG, 1HHJ, 1HHI and 1HHK, respectively) shows each individual water molecule in a different color. A comparison of the two-color schemes for each complex (cf. Fig. 3a with a'
, etc.) shows that some of the clusters result from a single water molecule (i.e. this water molecule retained an essentially similar location over the trajectory). Other clusters, in contrast, are made up of several different water molecules, suggesting an exchange process occurred during the simulation.
Our data suggest that the water in the groove of the hydrophilic peptides is disordered. In 1HHG the water network in the region between R97, D77 and p7 (the `green' water in Fig. 3a
) comprises many different water molecules at different points in the trajectory. This conclusion can be reached by examining Fig. 3
(a'), where it is apparent that multiple water molecules exchange into and out of this region over the trajectory. Other regions of the groove of 1HHG have somewhat more defined clusters of water molecules (Fig. 3a
). Multiple clusters (yellow) can be discerned associated with the p5 carbonyl and a further cluster (blue) is apparent close to R97. Some of these clusters (e.g. the left most yellow cluster in Fig. 3a
) are occupied by the same water molecule throughout the trajectory (the `blue' water molecule in Fig. 3a'
). However, based on Fig. 3
(a'), other clusters are occupied by different water molecules at different times in the trajectory and hence there is water exchange occurring between these sites. Similar conclusions can be drawn from examining the water network in the 1HHJ simulation (Fig. 3b and b'
).
The water networks in the complexes of the two hydrophobic peptides (1HHI and 1HHK) differ from those of the hydrophilic peptides. For 1HHI, there are discernable water clusters (Fig. 3c
). Two of these are associated with p5 (yellow), six with R97 (blue), two with p7 (green) and at least two with D77 (red). [We do not include the additional water molecule bound to D77 (the rightmost cluster in Fig. 3c
), which is detected by our analysis, but is not inside the binding groove.] Furthermore, most of the clusters are made up of only one water molecule throughout the simulation (cf. Fig. 3c and c'
). However, the water network is not completely rigid. In particular, the water clusters associated with p7 (those in green in Fig. 3c
) are made up of a number of different water molecules at different times in the trajectory (see below).
In 1HHK, several distinct clusters are seen (Fig. 3d
) and each of these sites is occupied by the same water molecule throughout the trajectory (Fig. 3d'
). Hence, 1HHK may be an example of a MHCpeptide complex of a very hydrophobic peptide in which the water molecules mediating the MHCpeptide interactions occupy relatively rigid binding sites.
We have analyzed the water dynamics for 1HHJ and 1HHI (Figs 4 and 5
respectively). These figures show the waterpeptide, waterprotein and waterwater hydrogen bonds that occur over the course of the trajectory, and allow the waterwater exchange processes discussed above to be displayed in greater detail. In Figs 4 and 5
, each circle represents the interactions of a specific amino acid of the MHC molecule or the peptide, as designated in the center of the circle, with one or more water molecules (each of which are assigned a specific color). The `top' of each circle represents 0 time and the trajectory progresses in a clockwise direction. A full circle (360°) represents 400 ps. The coloring of water molecules in Figs 4 and 5
is consistent with the color schemes used in Fig. 3
(b' and c') respectively. Waterwater hydrogen bonds are represented in a similar manner, with a given circle representing the interaction of one water molecule (defined by the colored disc in the circle center) with one or more different water molecules. The formation and breaking of hydrogen bonds in the trajectory is identified by a change in the color of the circle and the length of the hydrogen bond is related to the distance of individual points in the outer rings from the center of the circle.

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Fig. 4. Waterpeptide, waterprotein and waterwater hydrogen bonds formed in the molecular dynamics trajectory of 1HHJ. Each circle represents the interactions of one or more water molecules with a specific amino acid of the MHC molecule or the peptide (as designated in the center of the circle by the amino acid name) or with a specific water molecule (identified in the center of the circle by a colored disc). The `top' of each circle represents 0 time and the trajectory progresses in a clockwise direction. The total time is 400 ps The coloring of water molecules is consistent with the color schemes used in Fig. 3 (b').
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The hydrogen bonding of the groove water network and the water exchange processes in 1HHJ are shown in Fig. 4
. First, it is apparent (panels 13 of Fig. 4
) that the `green' water molecule forms a three-way bridge between D77, R97 and the p7 carbonyl group of the peptide. This interaction is also observable in Fig. 3
(b'). The `green' water molecule also interacts with the remainder of the water network through hydrogen bonding with a water molecule in a second site (panel 4, Fig. 4
). However, this latter site is occupied by two different water molecules (initially the `red' and then the `pink' water molecule). By considering the association of R97 and p7 with these same water molecules, it is apparent that this second site is also a bridge between R97 and p7 (panels 5 and 6, Fig. 4
). Hence, while water in this site mediates the peptideMHC interaction, it is also possible for water molecules to exchange into and out of the site. Furthermore, the molecule occupying this site interacts with other parts of the groove water network, as shown by the maintenance of the hydrogen bond between the `red'/`pink' combination and the `yellow' water molecule (panel 7, Fig. 4
). It is of note that all of the hydrogen-bonding interactions associated with the R97waterp7 bridge simultaneously change at ~120 ps of the trajectory (panels 47, Fig. 4
). In contrast to these relatively well-defined sites and exchange processes, much of the remaining groove water network is much more mobile. This is exemplified by the hydrogen-bonding interactions of the `blue' and `light blue' water molecules, which associate with multiple water molecules over the trajectory (panels 8 and 9, Fig. 4
).
In Fig. 5
we show a similar analysis of the 1HHI complex. The water network in 1HHI has more defined sites than that of IHHJ and many of these sites are occupied by only one water molecule. However, the water exchange processes described for 1HHJ still occur. These two aspects of the 1HHI water network are exemplified by the two-water bridge between the peptide p5 carbonyl group and R97 (panels 13, Fig. 5
). The site just below p5 is occupied by the `white' water molecule throughout the trajectory (Fig. 3c'
and panel 1, Fig. 5
). This water molecule forms a hydrogen bond with water molecules in a second site, which is occupied initially by the `blue' water and, subsequently, as the result of an exchange process, by the `gray' water molecule (panel 2, Fig. 5
), and this second site is also associated with R97 (panel 3, Fig. 5
).
At least four further solvation sites exist around R97 and the water molecules occupying these sites are also strongly hydrogen bonded with each other. The network defining these sites can be traced in Fig. 5
through the R97water interactions and waterwater interactions between the blue/gray, purple, brown, light yellow and light blue water molecules (panels 411, Fig. 5
). This network extends to a fifth site associated with R97 (panels 12 and 13, Fig. 5
), but this site (colored in blue in Fig. 3c
, to the upper right of the R97 side chain) is occupied by multiple water molecules (panel 13, Fig. 5
). This latter site is well defined, however, as shown by the conservation of hydrogen bonding between the water molecules occupying it and the `light blue' water molecule (note the similarity of coloring in the circles of panel 12 and 13, Fig. 5
).
The `light blue' water molecule also participates in a network involving three amino acids (R97, D77 and peptide p7) and four water molecules (light blue, pink, red/blue and green). This network can be seen in Fig. 3
(c') (in which the `pink' site is somewhat hidden by the red/blue site) and traced through examination of panels 1420 in Fig. 5
. Within this network, correlated exchange processes occur, as illustrated by simultaneous color changes (at ~270 ps) in panels 1618 in Fig. 5
.
Just before 200 ps of the simulation, several exchange processes occur such that there is a multiple rearrangement of occupancy of sites defined by panels 3, 13 and 21. The `yellow' water molecule moves from an R97 site (panel 13, Fig. 5
) to a p7 site (panel 21, Fig. 5
), where it remains only for a very short period. This motion results in the displacement of the `gray' water molecule, which moves into a second R97 site (panel 3, Fig. 5
) that is located directly above the R97 side chain (Fig. 3c and c'
). This displaces the `blue' water from this site and allows it to move into the first R97 site (panel 13, Fig. 5
), thus completing a cyclic movement of the `yellow', `gray' and `blue' water molecules. These three water molecules also hydrogen bond to each other during the simulation and form the more `dynamic' part of the water network.
A different aspect of the dynamic nature of the network is illustrated by an exchange process between the groove solvent and the bulk solvent. The `orange' water, which occupies the p7 site (panel 21, Fig. 5
) in the final 100 ps of the simulation, is not in the binding groove at the beginning of the simulation. This is shown by the absence of any interactions of the `orange' water with other binding groove water molecules in the first 240 ps of the simulation (panel 25, Fig. 5
). This water molecule enters the groove at ~240 ps by first associating with the carbonyl group of the peptide amino acid p5, in a location partially inside the binding groove. This association is lost at ~300 ps, when an exchange occurs with the `yellow' water molecule (panel 24, Fig. 4
). The association of the `yellow' water with p5 is retained until ~380 ps, at which point the `yellow' water dissociates and leaves the binding groove. It is of note that during this 300380 ps period there are very few hydrogen-bonding interactions of the `yellow' water with other water molecules in the binding groove (panel 23, Fig. 5
). Hence, the net result of the motions taking place between ~200 and 380 ps is to exchange a water molecule between the groove and the bulk solvent, with the `orange' water molecule moving into the groove and the `yellow' water molecule leaving the groove. The p5 site (panel 24, Fig. 5
) acts as an `entry point' for this exchange.
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Discussion
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It is well known that water can mediate ligandreceptor interactions. Examples of this phenomenon range from highly specific binding of a single water molecule (as in, for example, the well-known water molecule in many HIV protease/inhibitor complexes) to the occurrence of multiple water molecules at the ligandreceptor interface [as in, for example, the trp repressorDNA complex (32,33)]. Molecular dynamics simulations have provided a detailed description of water molecule exchange at the interface of the Antennapedia homeodomainDNA complex (34), based on NMR data (35). As an extension of this, it is increasingly being recognized that water molecules can modulate the specificity of ligandreceptor interactions. Examples of this include differences in DNA binding specificity between NF-
B p52 and NF-
B p50 homodimers (36), and of the estrogen receptor with consensus and non-consensus DNA sequences (37).
The presence of a similar water network at the MHCpeptide interface has been hinted at by several X-ray structures of MHCpeptide complexes, in which a few water molecules have been observed in the binding groove (12,13,17, 29,30,31,38). As for many other proteinligand complexes, these water molecules form water-bridged hydrogen bonds that mediate indirect MHCpeptide interactions. However, the presence of water molecules may also influence the peptide sequence that can be accommodated by the MHC molecule (17,31). Smith et al. (31) have discussed the potential role of these water molecules in mediating side chainside chain interactions. This could allow for modulation of the side chain positions and conformations and, in turn, it suggests how a given MHC molecule might be able to adjust its binding surface to accommodate different peptides. A specific example of this has been shown for the complexes of H-2Kb with peptides of sequence RGYVYQGL and SIINFEKL (17). The small side chain at position 2 of RGYVYQGL allows a water molecule to fit into the binding groove and mediate hydrogen bonding between the MHC molecule and the hydroxyl group of Y5. With SIINFEKL, this water cannot be similarly positioned because of the larger isoleucine side chain at position 2. Thus a phenylalanine, instead of a tyrosine, is favored at position 5.
In this paper, we have shown, based on molecular dynamics simulations, that water molecules at the MHCpeptide interface form a dynamic network that exhibits exchange within the binding groove and between the groove and the bulk solvent. The inclusion of these water molecules in models of peptideMHC binding may be important in increasing the reliability of such models. From a biological perspective, different numbers of water molecules are required for the binding of different peptide sequences and we propose that the groove water molecules allow the MHC molecule to alter the binding surface such that it can be complementary to a large set of diverse peptides. Such a mechanism would provide the MHC molecule with the potential for promiscuous binding that seems to be required for its biological role, while still maintaining a sufficiently high affinity for peptides for stable presentation to T cells.
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Acknowledgments
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We acknowledge funding from the NIH [PO1 HL60231, CA64299-01 (I. S. H.) and DK49717 (H. v. G.)]. Additional support was provided by a grant (H. v. G.) from the Pharmaceutical Manufacturers Association of America (PhARMA) Foundation. W. S. M. was supported by the Charles and Charlotte Krown Fellowship, and a grant from the American Foundation for Pharmaceutical Education. We thank the author of SURFNET for making the program available (http://www.biochem.ucl.ac.uk/~roman/surfnet/surfnet.html).
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Abbreviations
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Notes
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1 Present address: Department of Surgery, Division of Surgical Oncology, University of California at Los Angeles, 10833 LeConte Avenue, Los Angeles, CA 90095, USA 
2 Present address: Department of Medicine, BMT B11, University of Southern California, Los Angeles, CA 90033, USA 
Transmitting editor: T. Sasazuki
Received 6 December 1999,
accepted 3 March 2000.
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