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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 three simulated systems are structurally aligned for comparison. The SEC domain and Vb domain are shown in cartoon representation, with the mutated positions shown in licorice (hydrophobic residues in white, polar in green, negatively charged in red, positively charged in blue). An excerpt of the full sequence alignment is shown with mutated positions highlighted and numbered.
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fig1: The three simulated systems are structurally aligned for comparison. The SEC domain and Vb domain are shown in cartoon representation, with the mutated positions shown in licorice (hydrophobic residues in white, polar in green, negatively charged in red, positively charged in blue). An excerpt of the full sequence alignment is shown with mutated positions highlighted and numbered.

Mentions: An example of how mutations can induce intercalating water molecules and improve binding affinity is the engineering of a T-cell receptor mutant that binds staphylococcal enterotoxin 3 (SEC3) 1000 times more strongly than wild type(8) (Figure 1). These systems are exceptionally well characterized in terms of their binding, thermodynamics, and structures and are examples of protein‚ąíprotein systems that exhibit interfacial plasticity, cooperativity, and additivity among mutants. The effect of each TCR mutation (G17E, A52V, S54N, K66E, E80V, L81S, T87S, G96V) was analyzed via extensive kinetic and structural studies.9,10 In some cases, the affinity was additive, whereas in others it was cooperative.


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 three simulated systems are structurally aligned for comparison. The SEC domain and Vb domain are shown in cartoon representation, with the mutated positions shown in licorice (hydrophobic residues in white, polar in green, negatively charged in red, positively charged in blue). An excerpt of the full sequence alignment is shown with mutated positions highlighted and numbered.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: The three simulated systems are structurally aligned for comparison. The SEC domain and Vb domain are shown in cartoon representation, with the mutated positions shown in licorice (hydrophobic residues in white, polar in green, negatively charged in red, positively charged in blue). An excerpt of the full sequence alignment is shown with mutated positions highlighted and numbered.
Mentions: An example of how mutations can induce intercalating water molecules and improve binding affinity is the engineering of a T-cell receptor mutant that binds staphylococcal enterotoxin 3 (SEC3) 1000 times more strongly than wild type(8) (Figure 1). These systems are exceptionally well characterized in terms of their binding, thermodynamics, and structures and are examples of protein‚ąíprotein systems that exhibit interfacial plasticity, cooperativity, and additivity among mutants. The effect of each TCR mutation (G17E, A52V, S54N, K66E, E80V, L81S, T87S, G96V) was analyzed via extensive kinetic and structural studies.9,10 In some cases, the affinity was additive, whereas in others it was cooperative.

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.