Journal
JOURNAL OF COMPUTATIONAL CHEMISTRY
Volume 34, Issue 16, Pages 1398-1408Publisher
WILEY
DOI: 10.1002/jcc.23276
Keywords
GTP; local elevation; umbrella sampling; enhanced-sampling; one-step perturbation
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Funding
- Vienna Science and Technology Fund (WWTF) [LS08-QM03]
- European Research Council (ERC) [260408]
- European Research Council (ERC) [260408] Funding Source: European Research Council (ERC)
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Multiple conformations separated by high-energy barriers represent a challenging problem in free-energy calculations due to the difficulties in achieving adequate sampling. We present an application of thermodynamic integration (TI) in conjunction with the local elevation umbrella sampling (LE/US) method to improve convergence in alchemical free-energy calculations. TI-LE/US was applied to the guanosine triphosphate (GTP) to 8-Br-GTP perturbation, molecules that present high-energy barriers between the anti and syn states and that have inverted preferences for those states. The convergence and reliability of TI-LE/US was assessed by comparing with previous results using the enhanced-sampling one-step perturbation (OSP) method. A linear interpolation of the end-state biasing potentials was sufficient to dramatically improve sampling along the chosen reaction coordinate. Conformational free-energy differences were also computed for the syn and anti states and compared to experimental and theoretical results. Additionally, a coupled OSP with LE/US was carried out, allowing the calculation of conformational and alchemical free energies of GTP and 8-substituted GTP analogs. (c) 2013 Wiley Periodicals, Inc.
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