Pushing the boundaries of molecular replacement with maximum likelihood.

By Randy J. Read. 2001

799 citations recorded by the source corpus.

The molecular-replacement method works well with good models and simple unit cells, but often fails with more difficult problems. Experience with likelihood in other areas of crystallography suggests that it would improve performance significantly. For molecular replacement, the form of the required likelihood function depends on whether there is ambiguity in the relative phases of the contributions from symmetry-related molecules (e.g. rotation versus translation searches). Likelihood functions used in structure refinement are appropriate only for translation (or six-dimensional) searches, where the correct translation will place all of the atoms in the model approximately correctly. A new likelihood function that allows for unknown relative phases is suitable for rotation searches. It is shown that correlations between sequence identity and coordinate error can be used to calibrate parameters for model quality in the likelihood functions. Multiple models of a molecule can be combined in a statistically valid way by setting up the joint probability distribution of the true and model structure factors as a multivariate complex normal distribution, from which the conditional distribution of the true structure factor given the models can be derived. Tests in a new molecular-replacement program, Beast, show that the likelihood-based targets are more sensitive and more accurate than previous targets. The new multiple-model likelihood function has a dramatic impact on success.

Subfields: Computational Theory and Mathematics, Materials Chemistry, Spectroscopy

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Citations in the corpus

Local Error Estimates Dramatically Improve the Utility of Homology Models for Solving Crystal Structures by Molecular Replacement (2015, background): “LLG LLG measures how much better than a random model an atomic model explains the measured X-ray amplitudes (Read, 2001).”
A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS (2020, neutral): “REAGENT or RESOURCE SOURCE IDENTIFIER pCAGGS-SARS-CoV-2-RBD-sc-dimer-His, residues 319-537, two copies in tandem, accession number: YP_009724390 This paper N/A pCAGGS-SARS-CoV-RBD-His, residues 306-527, accession number: NP_828851 This paper N/A pCAGGS-SARS-RBD-sc-dimer-His, residues 306-523, two co”
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP (2008, methodology): “The structures were solved by molecular replacement method with PHASER (35), using the EGFR 696-1022 G719S structure [Protein Data Bank (PDB) ID code 2itn] (8) for apo-T790M and T790M/AEE788 structures and EGFR 696-1022 V948R structure (PDB code 2gs7) (9) for the T790M/HKI-272 structure.”
Ab initio solution of macromolecular crystal structures without direct methods (2017, methodology): “The resolution-dependent value of σA for each reflection can be estimated from the fraction (fP) of the X-ray scattering power accounted for by the model (where the total scattering power is the sum of the squares of the scattering factors for the atoms in the crystal), its estimated accuracy (rms e”
phenix.mr_rosetta: molecular replacement and model rebuilding with Phenix and Rosetta (2012, methodology): “These models are rescored with the Phaser log-likelihood scoring procedure [9] using a ﬁxed value of the estimated rmsd between template and target structure (typically using the smallest value of the estimated rmsd for all the search models considered).”
The utility of comparative models and the local model quality for protein crystal structure determination by Molecular Replacement (2012, background): “The placements are scored by an MR search function that measures the agreement between the theoretical and the observed structure factors [2-7].”
The Phenix Software for Automated Determination of Macromolecular Structures (2011, background): “The sensitivity of molecular replacement searches can also be improved by using a superimposed ensemble of alternative (but reasonably similar) models[39].”
Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. (2007, methodology): “All structures were solved by molecular replacement with PHASER (Read, 2001) using the approximately isomorphous apo-EGFR structure as the search model (PDB code 1M14 or 1M17) (Stamos et al., 2002).”
MUSTANG: A multiple structural alignment algorithm (2006, methodology): “Crystallographic packages such as PHASER [1, 2] can use ensembles of aligned structures as molecular replacement (MR) probes.”