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"Conditional Restraints": Restraining the Free Atoms in ARP/wARP.

ABSTRACT: The automated building of a protein model into an electron density map remains a challenging problem. In the ARP/wARP approach, model building is facilitated by initially interpreting a density map with free atoms of unknown chemical identity; all structural information for such chemically unassigned atoms is discarded. Here, this is remedied by applying restraints between free atoms, and between free atoms and a partial protein model. These are based on geometric considerations of protein structure and tentative (conditional) assignments for the free atoms. Restraints are applied in the REFMAC5 refinement program and are generated on an ad hoc basis, allowing them to fluctuate from step to step. A large set of experimentally phased and molecular replacement structures showcases individual structures where automated building is improved drastically by the conditional restraints. The concept and implementation we present can also find application in restraining geometries, such as hydrogen bonds, in low-resolution refinement.

SUBMITTER: Mooij WT

PROVIDER: S-EPMC2670983 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The absolute (standard) binding free energy of eight FK506-related ligands to FKBP12 is calculated using free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent. A number of features are implemented to improve the accuracy and enhance the convergence of the calculations. First, the absolute binding free energy is decomposed into sequential steps during which the ligand-surrounding interactions as well as various biasing potentials restraining the translation, orientation, and conformation of the ligand are turned "on" and "off." Second, sampling of the ligand conformation is enforced by a restraining potential based on the root mean-square deviation relative to the bound state conformation. The effect of all the restraining potentials is rigorously unbiased, and it is shown explicitly that the final results are independent of all artificial restraints. Third, the repulsive and dispersive free energy contribution arising from the Lennard-Jones interactions of the ligand with its surrounding (protein and solvent) is calculated using the Weeks-Chandler-Andersen separation. This separation also improves convergence of the FEP/MD calculations. Fourth, to decrease the computational cost, only a small number of atoms in the vicinity of the binding site are simulated explicitly, while all the influence of the remaining atoms is incorporated implicitly using the generalized solvent boundary potential (GSBP) method. With GSBP, the size of the simulated FKBP12/ligand systems is significantly reduced, from approximately 25,000 to 2500. The computations are very efficient and the statistical error is small ( approximately 1 kcal/mol). The calculated binding free energies are generally in good agreement with available experimental data and previous calculations (within approximately 2 kcal/mol). The present results indicate that a strategy based on FEP/MD simulations of a reduced GSBP atomic model sampled with conformational, translational, and orientational restraining potentials can be computationally inexpensive and accurate.

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"Conditional Restraints": Restraining the Free Atoms in ARP/wARP.

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