Buried waters and internal cavities in monomeric proteins

Abstract

We have analyzed the buried water molecules and internal cavities in a set of 75 high-resolution, nonhomologous, monomeric protein structures. The number of hydrogen bonds formed between each water molecule and the protein varies from 0 to 4, with 3 being most common. Nearly half of the water molecules are found in pairs or larger clusters. Approximately 90% are shown to be associated with large cavities within the protein, as determined by a novel program, PRO-ACT. The total volume of a protein's large cavities is proportional to its molecular weight and is not dependent on structural class. The largest cavities in proteins are generally elongated rather than globular. There are many more empty cavities than hydrated cavities. The likelihood of a cavity being occupied by a water molecule increases with cavity size and the number of available hydrogen bond partners, with each additional partner typically stabilizing the occupied state by 0.6 kcal/mol.

The Multiple Roles of Waters in Protein Solvation

“…Figure S4). In fact for folded proteins we found one "permanently bound" water every 10-21 residues, consistent with Williams' estimates 43 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2), to a small increase in the number of tightly bound and frequently interacting water molecules, compared with the simulation in pure water at the same temperature, which can be attributed mostly (see Figure 3) to a greater relative hydrophilicity of charged residues. Finally, PEG leads to a very significant increase in the percentage of water molecules that are tightly bound to the protein (surface waters increase from 0.3-0.5% in pure water to 2-3 % in the presence of PEG;…”

Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design

“…Research toward this end includes analytical area and volume calculation (Connolly, 1983;Richmond, 1984;Gibson & Scheraga, 1987); cavity identification and measurement (Rashin et al, 1986;Voorintholt et al, 1989;Ho & Marshall, 1990;Alard & Wodak, 1991;Nicholls et al, 1993;Smart et al, 1993;Hubbard et al, 1994;Kleywegt & Jones, 1994;Williams et al, 1994); pocket or cleft computation (Kuntz et al, 1982;Delaney, 1992;Levitt & Banaszak, 1992;Laskowski, 1995;Peters et al, 1996); and molecular shape representation (Lin et al, 1994). Although useful, their application to pocket calculations is limited by lack of fully automatic computations, lack of analytical measurements of area and volume with real physical meaning, and/or use of arbitrarily adjusted parameters.…”

StoneHinge: Hinge prediction by network analysis of individual protein structures

“…27 All predictions presented here are made with internal water molecules only, as determined by PRO_ACT. 47 Predictions were also run using no water molecules (data not shown), as is done on the automated StoneHinge server. Although the overall flexibility analysis changed slightly, the hinge predictions were largely the same.…”