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Dynamical view of the positions of key side chains in protein-protein recognition.

ABSTRACT: When a complex is constructed from the separately determined rigid structures of a receptor and its ligand, some key side chains are usually in wrong positions. These distortions of the interface yield an apparent loss in affinity and would unfavorably affect the kinetics of association. It is generally assumed that the interacting proteins should drive the appropriate conformational changes, leading to their complementarity, but this hypothesis does not explain their fast association rates. However, nanosecond explicit solvent molecular dynamics simulations of misfolded surface side chains from the independently solved structures of barstar, bovine pancreatic trypsin inhibitor, and lysozyme show that even before any receptor-ligand interaction, key side chains frequently visit the rotamer conformations seen in the complex. We show that these simple structural motifs can reconcile most of the binding affinity required for a rapid and highly specific association process. Side chains amenable to induced fit are also identified. These results corroborate that solvent-side chain interactions play a critical role in the recognition process. Our findings are also supported by crystallographic data.

SUBMITTER: Kimura SR

PROVIDER: S-EPMC1301263 | biostudies-other | 2001 Feb

REPOSITORIES: biostudies-other

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Dynamical view of the positions of key side chains in protein-protein recognition.

Kimura S R SR Brower R C RC Vajda S S Camacho C J CJ

Biophysical journal 20010201 2

When a complex is constructed from the separately determined rigid structures of a receptor and its ligand, some key side chains are usually in wrong positions. These distortions of the interface yield an apparent loss in affinity and would unfavorably affect the kinetics of association. It is generally assumed that the interacting proteins should drive the appropriate conformational changes, leading to their complementarity, but this hypothesis does not explain their fast association rates. How ...[more]

PMID: 11159432

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Project description:INTRODUCTION: The accurate packing of protein side chains is important for many computational biology problems, such as ab initio protein structure prediction, homology modelling, and protein design and ligand docking applications. Many of existing solutions are modelled as a computational optimisation problem. As well as the design of search algorithms, most solutions suffer from an inaccurate energy function for judging whether a prediction is good or bad. Even if the search has found the lowest energy, there is no certainty of obtaining the protein structures with correct side chains. METHODS: We present a side-chain modelling method, pacoPacker, which uses a parallel ant colony optimisation strategy based on sharing a single pheromone matrix. This parallel approach combines different sources of energy functions and generates protein side-chain conformations with the lowest energies jointly determined by the various energy functions. We further optimised the selected rotamers to construct subrotamer by rotamer minimisation, which reasonably improved the discreteness of the rotamer library. RESULTS: We focused on improving the accuracy of side-chain conformation prediction. For a testing set of 442 proteins, 87.19% of X1 and 77.11% of X12 angles were predicted correctly within 40° of the X-ray positions. We compared the accuracy of pacoPacker with state-of-the-art methods, such as CIS-RR and SCWRL4. We analysed the results from different perspectives, in terms of protein chain and individual residues. In this comprehensive benchmark testing, 51.5% of proteins within a length of 400 amino acids predicted by pacoPacker were superior to the results of CIS-RR and SCWRL4 simultaneously. Finally, we also showed the advantage of using the subrotamers strategy. All results confirmed that our parallel approach is competitive to state-of-the-art solutions for packing side chains. CONCLUSIONS: This parallel approach combines various sources of searching intelligence and energy functions to pack protein side chains. It provides a frame-work for combining different inaccuracy/usefulness objective functions by designing parallel heuristic search algorithms.

Dataset Information

Dynamical view of the positions of key side chains in protein-protein recognition.

Publications

Dynamical view of the positions of key side chains in protein-protein recognition.

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