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Computational methods for predicting sites of functionally important dynamics.

ABSTRACT: Understanding and controlling biological function of proteins at the atomic level is of great importance; allosteric mechanisms provide such an interface. Experimental and computational methods have been developed to search for residue mutations that produce changes in function by altering sites of correlated motion. These methods are often observational in that altered motions are achieved by random sampling without revealing the underlying mechanism(s). We present two deterministic methods founded on structure-function relationships that predict dynamic control sites (i.e., locations that experience correlated motions as a result of altered dynamics). The first method ("static") is based on a single structure conformation (e.g., the wild type (WT)) and utilizes a graph description of atomic connectivity. The local atomic interactions are used to compute the propagation of contact paths. This description of structure connectivity reveals flexible locations that are susceptible to altered dynamics. The second method ("dynamic") is a comparative analysis between the normal modes of a WT structure and a mutant structure. A mapping function is defined that quantifies the significance of the motions in one structure projected onto the motions of the other. Each mode is considered up- or down-regulated according to its change in relative significance. This description of altered dynamics is the basis for a motion correlation analysis, from which the dynamic control sites are readily identified. The methods are theoretically derived and applied using the canonical system dihydrofolate reductase (DHFR). Both methods demonstrate a very high predictive value (p<0.005) in identifying known dynamic control sites. The dynamic method also produces a new hypothesis regarding the mechanism by which the DHFR mutant achieves hyperactivity. These tools are suitable for allosteric investigations and may greatly enhance the speed and effectiveness of other computational and experimental methods.

SUBMITTER: Schuyler AD

PROVIDER: S-EPMC2761153 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Computational methods for predicting sites of functionally important dynamics.

Schuyler Adam D AD Carlson Heather A HA Feldman Eva L EL

The journal of physical chemistry. B 20090501 19

Understanding and controlling biological function of proteins at the atomic level is of great importance; allosteric mechanisms provide such an interface. Experimental and computational methods have been developed to search for residue mutations that produce changes in function by altering sites of correlated motion. These methods are often observational in that altered motions are achieved by random sampling without revealing the underlying mechanism(s). We present two deterministic methods fou ...[more]

PMID: 19378962

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Project description:BACKGROUND: The identification of functionally or structurally important non-conserved residue sites in protein MSAs is an important challenge for understanding the structural basis and molecular mechanism of protein functions. Despite the rich literature on compensatory mutations as well as sequence conservation analysis for the detection of those important residues, previous methods often rely on classical information-theoretic measures. However, these measures usually do not take into account dis/similarities of amino acids which are likely to be crucial for those residues. In this study, we present a new method, the Quantum Coupled Mutation Finder (QCMF) that incorporates significant dis/similar amino acid pair signals in the prediction of functionally or structurally important sites. RESULTS: The result of this study is twofold. First, using the essential sites of two human proteins, namely epidermal growth factor receptor (EGFR) and glucokinase (GCK), we tested the QCMF-method. The QCMF includes two metrics based on quantum Jensen-Shannon divergence to measure both sequence conservation and compensatory mutations. We found that the QCMF reaches an improved performance in identifying essential sites from MSAs of both proteins with a significantly higher Matthews correlation coefficient (MCC) value in comparison to previous methods. Second, using a data set of 153 proteins, we made a pairwise comparison between QCMF and three conventional methods. This comparison study strongly suggests that QCMF complements the conventional methods for the identification of correlated mutations in MSAs. CONCLUSIONS: QCMF utilizes the notion of entanglement, which is a major resource of quantum information, to model significant dissimilar and similar amino acid pair signals in the detection of functionally or structurally important sites. Our results suggest that on the one hand QCMF significantly outperforms the previous method, which mainly focuses on dissimilar amino acid signals, to detect essential sites in proteins. On the other hand, it is complementary to the existing methods for the identification of correlated mutations. The method of QCMF is computationally intensive. To ensure a feasible computation time of the QCMF's algorithm, we leveraged Compute Unified Device Architecture (CUDA).The QCMF server is freely accessible at http://qcmf.informatik.uni-goettingen.de/.

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Computational methods for predicting sites of functionally important dynamics.

Publications

Computational methods for predicting sites of functionally important dynamics.

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