Classification of Water Molecules in Protein Binding Sites

Barillari, Caterina; Taylor, Justine; Viner, Russell; Essex, Jonathan W.

doi:10.1021/ja066980q

Cited by 276 publications

(404 citation statements)

References 57 publications

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“…It also reflects our reluctance to optimize the weighting of the scoring function terms for optimal retrospective performance, aware of the oft-described tradeoffs between retrospective optimization and prospective prediction (49). Finally, it is worth noting that in implementing GIST, we only considered the energetic consequences of displacing ordered waters, and did not model the specific interactions between ligands and such waters, which play a role in most protein-ligand complexes (6,7,38,50,51). Here, such interacting waters, which can appear with a ligand to bridge between it and the protein surface, were only implicitly modeled as high-energy, hard-to-displace regions.…”

Section: Discussionmentioning

confidence: 99%

Testing inhomogeneous solvation theory in structure-based ligand discovery

Balius

Fischer

Stein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Binding-site water is often displaced upon ligand recognition, but is commonly neglected in structure-based ligand discovery. Inhomogeneous solvation theory (IST) has become popular for treating this effect, but it has not been tested in controlled experiments at atomic resolution. To do so, we turned to a grid-based version of this method, GIST, readily implemented in molecular docking. Whereas the term only improves docking modestly in retrospective ligand enrichment, it could be added without disrupting performance. We thus turned to prospective docking of large libraries to investigate GIST's impact on ligand discovery, geometry, and water structure in a model cavity site well-suited to exploring these terms. Although top-ranked docked molecules with and without the GIST term often overlapped, many ligands were meaningfully prioritized or deprioritized; some of these were selected for testing. Experimentally, 13/14 molecules prioritized by GIST did bind, whereas none of the molecules that it deprioritized were observed to bind. Nine crystal complexes were determined. In six, the ligand geometry corresponded to that predicted by GIST, for one of these the pose without the GIST term was wrong, and three crystallographic poses differed from both predictions. Notably, in one structure, an ordered water molecule with a high GIST displacement penalty was observed to stay in place. Inclusion of this water-displacement term can substantially improve the hit rates and ligand geometries from docking screens, although the magnitude of its effects can be small and its impact in drug binding sites merits further controlled studies.water | inhomogeneous solvation theory | ligand discovery | structure-based drug design | docking T he treatment of receptor-bound water molecules, which are crucial for ligand recognition, is a widely recognized challenge in structure-based discovery (1-4). The more tightly bound a water in a site, the greater the penalty for its displacement upon ligand binding, ultimately leading to its retention and the adoption of ligand geometries that do not displace it. More problematic still is when a new bridging water mediates interactions between the ligand and the receptor. Because the energetics of bound water molecules have been challenging to calculate and bridging waters hard to anticipate, large-scale docking of chemical libraries has typically been conducted against artificially desolvated sites or has kept a handful of ordered water molecules that are treated as part of the site, based on structural precedence (5-8).Recently, several relatively fast approaches, pragmatic for early discovery, have been advanced to account for the differential displacement energies of bound water molecules (9-20), complementing more rigorous but computationally expensive approaches (18)(19)(20)(21)(22). Among the most popular of these has been inhomogeneous solvation theory (IST) (23)(24)(25). IST uses populations from molecular dynamics (MD) simulations on protein (solute) surfaces to calculate the cost of di...

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Section: Discussionmentioning

confidence: 99%

Testing inhomogeneous solvation theory in structure-based ligand discovery

Balius

Fischer

Stein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…7 If bulk water was found to have occupied the decoupled site during a simulation, the simulation was repeated with a hard-wall constraint applied to the decoupled water molecule as previously described. 8,59 The final set of restraints and constraints for each water molecule are shown in Tables S7 and S8.…”

Section: Free Energy Calculationsmentioning

confidence: 99%

Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo

2015

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Water molecules play integral roles in the formation of many protein-ligand complexes, and recent computational efforts have been focused on predicting the thermodynamic properties of individual waters and how they may be exploited in rational drug design. However, when water molecules form highly coupled hydrogen bonding networks, there is, as yet, no method that can rigorously calculate the free energy to bind the entire network, or assess the degree of cooperativity between waters. In this work, we report theoretical and methodological developments to the grand canonical Monte Carlo simulation technique. Central to our results is a rigorous equation that can be used to calculate efficiently the binding free energies of water networks of arbitrary size and complexity. Using a single set of simulations, our methods can locate waters, estimate their binding affinities, capture the cooperativity of the water network, and evaluate the hydration free energy of entire protein binding sites. Our techniques have been applied to multiple test systems and compare favourably to thermodynamic integra- *

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“…5d) and in the Pins-dInsc complex (data not shown). It is known that water molecules can stabilize the complex between a protein and its ligand by hydrogen bonding to the two components and can also sculpt the protein surface to improve interface complementarity (Barillari et al, 2007;Meenan et al, 2010).…”

Section: Recognition Of Various Partners By the Lgn Tpr Domainmentioning

confidence: 99%

Structural basis for the recognition of the scaffold protein Frmpd4/Preso1 by the TPR domain of the adaptor protein LGN

2015

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The adaptor protein LGN interacts via the N-terminal domain comprising eight tetratricopeptide-repeat (TPR) motifs with its partner proteins mInsc, NuMA, Frmpd1 and Frmpd4 in a mutually exclusive manner. Here, the crystal structure of the LGN TPR domain in complex with human Frmpd4 is described at 1.5 Å resolution. In the complex, the LGN-binding region of Frmpd4 (amino-acid residues 990-1011) adopts an extended structure that runs antiparallel to LGN along the concave surface of the superhelix formed by the TPR motifs.Comparison with the previously determined structures of the LGN-Frmpd1, LGN-mInsc and LGN-NuMA complexes reveals that these partner proteins interact with LGN TPR1-6 via a common core binding region with consensus sequence (E/Q)XEX 4-5 (E/D/Q)X 1-2 (K/R)X 0-1 (V/I). In contrast to Frmpd1, Frmpd4 makes additional contacts with LGN via regions N-and C-terminal to the core sequence. The N-terminal extension is replaced by a specific -helix in mInsc, which drastically increases the direct contacts with LGN TPR7/8, consistent with the higher affinity of mInsc for LGN. A crystal structure of Frmpd4-bound LGN in an oxidized form is also reported, although oxidation does not appear to strongly affect the interaction with Frmpd4.

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Classification of Water Molecules in Protein Binding Sites

Cited by 276 publications

References 57 publications

Testing inhomogeneous solvation theory in structure-based ligand discovery

Testing inhomogeneous solvation theory in structure-based ligand discovery

Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo

Structural basis for the recognition of the scaffold protein Frmpd4/Preso1 by the TPR domain of the adaptor protein LGN

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