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A Multilevel Strategy for the Exploration of the Conformational Flexibility of Small Molecules
journal contribution
posted on 2012-05-08, 00:00 authored by Flavio Forti, Claudio
N. Cavasotto, Modesto Orozco, Xavier Barril, F. Javier LuquePredicting the conformational preferences of flexible
compounds
is still a challenging problem with important implications in areas
such as molecular recognition and drug design. In this work, we describe
a multilevel strategy to explore the conformational preferences of
molecules. The method relies on the predominant-state approximation,
which partitions the conformational space into distinct conformational
wells. Moreover, it combines low-level (LL) methods for sampling the
conformational minima and high-level (HL) techniques for calibrating
their relative stability. In the implementation used in this study,
the LL sampling is performed with the semiempirical RM1 Hamiltonian,
and solvent effects are included using the RM1 version of the MST
continuum solvation model. The HL refinement of the conformational
wells is performed by combining geometry optimizations of the minima
at the B3LYP (gas phase) or MST-B3LYP (solution) level, followed by
single point MP2 computations using Dunning’s augmented basis
sets. Then, the effective free energy of a conformational well is
estimated by combining the MP2 energy, supplemented with the MST-B3LYP
solvation free energy for a conformational search in solution, with
the local curvature of the well sampled at the semiempirical level.
Applications of this strategy involve the exploration of the conformational
preferences of 1,2-dichloroethane and neutral histamine in both the
gas phase and water solution. Finally, the multilevel strategy is
used to estimate the reorganization cost required for selecting the
bioactive conformation of HIV reverse transcriptase inhibitors, which
is estimated to be at most 1.3 kcal/mol.