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The University of Southampton

Research project: Essex: The simulation of rare conformational change events in proteins

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Conformational change in protein systems is frequently an integral part of the protein’s function. Obtaining an understanding of these events, particularly in the absence of detailed experimental data, is obviously of intrinsic academic interest, but it is also important in the context of ligand design.

A novel binding mode for a drug may be associated with blocking these conformational changes, rather than, as is conventionally supposed, the blocking of the substrate binding pocket. An example of such a class of compound is the non-nucleoside reverse transcriptase inhibitors of HIV-reverse transcriptase. Modelling conformational changes is very difficult since by their nature they tend to occur only rarely. As a solution to this problem, we have developed a technique to modify the course of a molecular dynamics computer simulation. The method involves the first controlled application of digital signal processing (DSP) methods to the simulation velocities, and allows the atomic motion to be enhanced or suppressed in a selective manner solely on the basis of vibrational frequency (J. Phys. Chem. B 107, 2003, 2098-2110). This methodology has been successfully applied to the simulation of the conformational changes in lysozyme, dihydrofolate reductase, and HIV-protease (J. Chem. Theory Comput. 1, 2005, 24-35), and is now being extended to the study of the role of drug resistant mutations in protein dynamics. The analysis of these simulations is being assisted by the application of the recently developed Hilbert-Huang Transform, to allow the amplitude of molecular vibrations over defined frequency ranges to be calculated as a function of time (J. Phys. Chem. A 107, 2003, 4869-4876).

The main disadvantage of techniques based on DSP is that the outcome of digital amplification is inevitably a non-equilibrium distribution. We are therefore testing the Replica Exchange approach to enhancing protein motion (Phil. Trans. R. Soc. Lond. A 363, 2005, 2017-2035). We are also currently examining hybrid molecular dynamics / Monte Carlo simulation methods as an alternative approach to correcting the bias inherent in the digital filtering. With this approach we are able to increase the amount of conformational sampling, while retaining the underlying statistical ensemble. The potential for the DSP based approach is enormous. First, it is very computationally efficient, generating protein conformations far more rapidly than conventional molecular dynamics simulations. Second, unlike many approaches for modelling conformational change, it only requires one of the accessible protein conformations. Finally, its use may extend beyond conformational analysis through to, for example, generating receptor conformations for virtual screening in the context of rational drug design.

An alternative approach to sampling protein conformations is to simplify the underlying potential energy surface by combining groups of atoms into single interaction sites. We are investigating these coarse-grain protein models to determine the extent to which they are able to capture protein dynamics.

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The opening of the M20 loop in dihydrofolate reductase using digital filtering.

Related research groups

Computational Systems Chemistry
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