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MM-PBSA Captures Key Role of Intercalating Water Molecules at a Protein-Protein Interface.

Wong S, Amaro RE, McCammon JA - J Chem Theory Comput (2009)

Bottom Line: The T-cell receptor (TCR) and its staphylococcal enterotoxin 3 (SEC3) binding partner are well-characterized examples of a protein-protein interaction system exhibiting interfacial plasticity, cooperativity, and additivity among mutants.Specifically engineered mutants induce intercalating interfacial water molecules, which subsequently enhance protein-protein binding affinity.The results presented here point to the promise of MM-PBSA toward rationalizing molecular recognition at protein-protein interfaces, while establishing a general approach to handle explicit interfacial water molecules in such calculations.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, Department of Pharmacology, and Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093-0365.

ABSTRACT
The calculation of protein interaction energetics is of fundamental interest, yet accurate quantities are difficult to obtain due to the complex and dynamic nature of protein interfaces. This is further complicated by the presence of water molecules, which can exhibit transient interactions of variable duration and strength with the protein surface. The T-cell receptor (TCR) and its staphylococcal enterotoxin 3 (SEC3) binding partner are well-characterized examples of a protein-protein interaction system exhibiting interfacial plasticity, cooperativity, and additivity among mutants. Specifically engineered mutants induce intercalating interfacial water molecules, which subsequently enhance protein-protein binding affinity. In this work, we perform a set of molecular mechanics (MM) Poisson-Boltzmann (PB) surface area (SA) calculations on the wild type and two mutant TCR-SEC3 systems and show that the method is able to discriminate between weak and strong binders only when key explicit water molecules are included in the analysis. The results presented here point to the promise of MM-PBSA toward rationalizing molecular recognition at protein-protein interfaces, while establishing a general approach to handle explicit interfacial water molecules in such calculations.

No MeSH data available.


The S54N mutation stabilizes a water-mediated contact. A) Ser54 makes a water medicated contact with the backbone carbonyl of SEC3 Phe206. B) Ser54 in a conformation where the contact is broken. C) Asn54 making the water-mediated contact and also a hydrogen bond interaction with Asp56.
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fig2: The S54N mutation stabilizes a water-mediated contact. A) Ser54 makes a water medicated contact with the backbone carbonyl of SEC3 Phe206. B) Ser54 in a conformation where the contact is broken. C) Asn54 making the water-mediated contact and also a hydrogen bond interaction with Asp56.

Mentions: In the second case, we focus on fewer, specific water molecules that were suggested by the crystal structures to mediate contacts between residues Asn54 and Glu56 of TCR with the backbone amide of SEC3 Phe206 (Figure 2). To do that, at each trajectory snapshot, the shortest distance from each water molecule to TCR residues 54, 56, and SEC 206 was computed. For each water molecule, the square of the minimum distance to each of the residues was summed. This sum was used as a metric of how close any given water molecule was to the site of interaction. This list was sorted, and the two water molecules with the smallest sum of squared distances were chosen as the bridging water molecules for each snapshot. The same procedure was followed for the wild type and mutant trajectories; the two interface waters closest to TCR residues 54 and 56 and SEC3 residue 206 were included in the wild type calculation. The intercalating water molecules were considered part of SEC3 for the purposes of the MM-PBSA calculations.


MM-PBSA Captures Key Role of Intercalating Water Molecules at a Protein-Protein Interface.

Wong S, Amaro RE, McCammon JA - J Chem Theory Comput (2009)

The S54N mutation stabilizes a water-mediated contact. A) Ser54 makes a water medicated contact with the backbone carbonyl of SEC3 Phe206. B) Ser54 in a conformation where the contact is broken. C) Asn54 making the water-mediated contact and also a hydrogen bond interaction with Asp56.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2651627&req=5

fig2: The S54N mutation stabilizes a water-mediated contact. A) Ser54 makes a water medicated contact with the backbone carbonyl of SEC3 Phe206. B) Ser54 in a conformation where the contact is broken. C) Asn54 making the water-mediated contact and also a hydrogen bond interaction with Asp56.
Mentions: In the second case, we focus on fewer, specific water molecules that were suggested by the crystal structures to mediate contacts between residues Asn54 and Glu56 of TCR with the backbone amide of SEC3 Phe206 (Figure 2). To do that, at each trajectory snapshot, the shortest distance from each water molecule to TCR residues 54, 56, and SEC 206 was computed. For each water molecule, the square of the minimum distance to each of the residues was summed. This sum was used as a metric of how close any given water molecule was to the site of interaction. This list was sorted, and the two water molecules with the smallest sum of squared distances were chosen as the bridging water molecules for each snapshot. The same procedure was followed for the wild type and mutant trajectories; the two interface waters closest to TCR residues 54 and 56 and SEC3 residue 206 were included in the wild type calculation. The intercalating water molecules were considered part of SEC3 for the purposes of the MM-PBSA calculations.

Bottom Line: The T-cell receptor (TCR) and its staphylococcal enterotoxin 3 (SEC3) binding partner are well-characterized examples of a protein-protein interaction system exhibiting interfacial plasticity, cooperativity, and additivity among mutants.Specifically engineered mutants induce intercalating interfacial water molecules, which subsequently enhance protein-protein binding affinity.The results presented here point to the promise of MM-PBSA toward rationalizing molecular recognition at protein-protein interfaces, while establishing a general approach to handle explicit interfacial water molecules in such calculations.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, Department of Pharmacology, and Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093-0365.

ABSTRACT
The calculation of protein interaction energetics is of fundamental interest, yet accurate quantities are difficult to obtain due to the complex and dynamic nature of protein interfaces. This is further complicated by the presence of water molecules, which can exhibit transient interactions of variable duration and strength with the protein surface. The T-cell receptor (TCR) and its staphylococcal enterotoxin 3 (SEC3) binding partner are well-characterized examples of a protein-protein interaction system exhibiting interfacial plasticity, cooperativity, and additivity among mutants. Specifically engineered mutants induce intercalating interfacial water molecules, which subsequently enhance protein-protein binding affinity. In this work, we perform a set of molecular mechanics (MM) Poisson-Boltzmann (PB) surface area (SA) calculations on the wild type and two mutant TCR-SEC3 systems and show that the method is able to discriminate between weak and strong binders only when key explicit water molecules are included in the analysis. The results presented here point to the promise of MM-PBSA toward rationalizing molecular recognition at protein-protein interfaces, while establishing a general approach to handle explicit interfacial water molecules in such calculations.

No MeSH data available.