We report on the organization and outcome of the fourth blind test of crystal structure prediction, an international collaborative project organized to evaluate the present state in computational methods of predicting the crystal structures of small organic molecules. There were 14 research groups which took part, using a variety of methods to generate and rank the most likely crystal structures for four target systems: three single-component crystal structures and a 1:1 cocrystal. Participants were challenged to predict the crystal structures of the four systems, given only their molecular diagrams, while the recently determined but as-yet unpublished crystal structures were withheld by an independent referee. Three predictions were allowed for each system. The results demonstrate a dramatic improvement in rates of success over previous blind tests; in total, there were 13 successful predictions and, for each of the four targets, at least two groups correctly predicted the observed crystal structure. The successes include one participating group who correctly predicted all four crystal structures as their first ranked choice, albeit at a considerable computational expense. The results reflect important improvements in modelling methods and suggest that, at least for the small and fairly rigid types of molecules included in this blind test, such calculations can be constructively applied to help understand crystallization and polymorphism of organic molecules.

A collaborative workshop was held in May 1999 at the Cambridge Crystallographic Data Centre to test how well currently available methods of crystal structure prediction perform when given only the atomic connectivity for an organic compound. A blind test was conducted on a selection of four compounds and a wide range of methodologies representing, the principal computer programs currently available were used. There were 11 participants who were allowed to propose at most three structures for each compound. No program gave consistently reliable results. However, seven proposed structures were close to an experimental one and were classified as "correct". One compound occurred in two polymorphs, but only one form was predicted correctly among the calculated structures. The basic problem with lattice energy based methods of crystal structure prediction is that many structures are found within a few kJ mol(-1) of the global minimum. The fine detail of the force-field methodology and parametrization influences the energy ranking within each method. Nevertheless, present methods may be useful in providing a set of structures as possible polymorphs for a given molecular structure.

Following the interest generated by two previous blind tests of crystal structure prediction (CSP1999 and CSP2001), a third such collaborative project (CSP2004) was hosted by the Cambridge Crystallographic Data Centre. A range of methodologies used in searching for and ranking the likelihood of predicted crystal structures is represented amongst the 18 participating research groups, although most are based on the global minimization of the lattice energy. Initially the participants were given molecular diagrams of three molecules and asked to submit three predictions for the most likely crystal structure of each. Unlike earlier blind tests, no restriction was placed on the possible space group of the target crystal structures. Furthermore, Z' = 2 structures were allowed. Part-way through the test, a partial structure report was discovered for one of the molecules, which could no longer be considered a blind test. Hence, a second molecule from the same category (small, rigid with common atom types) was offered to the participants as a replacement. Success rates within the three submitted predictions were lower than in the previous tests - there was only one successful prediction for any of the three ;blind' molecules. For the ;simplest' rigid molecule, this lack of success is partly due to the observed structure crystallizing with two molecules in the asymmetric unit. As in the 2001 blind test, there was no success in predicting the structure of the flexible molecule. The results highlight the necessity for better energy models, capable of simultaneously describing conformational and packing energies with high accuracy. There is also a need for improvements in search procedures for crystals with more than one independent molecule, as well as for molecules with conformational flexibility. These are necessary requirements for the prediction of possible thermodynamically favoured polymorphs. Which of these are actually realised is also influenced by as yet insufficiently understood processes of nucleation and crystal growth.

The first collaborative workshop on crystal structure prediction (CSP1999) has been followed by a second workshop (CSP2001) held at the Cambridge Crystallographic Data Centre. The 17 participants were given only the chemical diagram for three organic molecules and were invited to test their prediction programs within a range of named common space groups. Several different computer programs were used, using the methodology wherein a molecular model is used to construct theoretical crystal structures in given space groups, and prediction is usually based on the minimum calculated lattice energy. A maximum of three predictions were allowed per molecule. The results showed two correct predictions for the first molecule, four for the second molecule and none for the third molecule (which had torsional flexibility). The correct structure was often present in the sorted low-energy lists from the participants but at a ranking position greater than three. The use of non-indexed powder diffraction data was investigated in a secondary test, after completion of the ab initio submissions. Although no one method can be said to be completely reliable, this workshop gives an objective measure of the success and failure of current methodologies.

Average bond distances and bond angles in carboxylic esters with different substitution patterns have been derived by analyzing data from many crystal structures retrieved from the Cambridge Structural Database (CSD). Conformation‐al preferences in the attachment of substituents are found.

Medical investigations targeting a quantitative analysis of the position emission tomography (PET) images require the incorporation of additional knowledge about the photon attenuation distribution in the patient. Today, energy range adapted attenuation maps derived from computer tomography (CT) scans are used to effectively compensate for image quality degrading effects, such as attenuation and scatter. Replacing CT by magnetic resonance (MR) is considered as the next evolutionary step in the field of hybrid imaging systems. However, unlike CT, MR does not measure the photon attenuation and thus does not provide an easy access to this valuable information. Hence, many research groups currently investigate different technologies for MR-based attenuation correction (MR-AC). Typically, these approaches are based on techniques such as special acquisition sequences (alone or in combination with subsequent image processing), anatomical atlas registration, or pattern recognition techniques using a data base of MR and corresponding CT images. We propose a generic iterative reconstruction approach to simultaneously estimate the local tracer concentration and the attenuation distribution using the segmented MR image as anatomical reference. Instead of applying predefined attenuation values to specific anatomical regions or tissue types, the gamma attenuation at 511 keV is determined from the PET emission data. In particular, our approach uses a maximum-likelihood estimation for the activity and a gradient-ascent based algorithm for the attenuation distribution. The adverse effects of scattered and accidental gamma coincidences on the quantitative accuracy of PET, as well as artifacts caused by the inherent crosstalk between activity and attenuation estimation are efficiently reduced using enhanced decay event localization provided by time-of-flight PET, accurate correction for accidental coincidences, and a reduced number of unknown attenuation coefficients. First results achieved with measured whole body PET data and reference segmentation from CT showed an absolute mean difference of 0.005 cm⁻¹ (< 20%) in the lungs, 0.0009 cm⁻¹ (< 2%) in case of fat, and 0.0015 cm⁻¹ (< 2%) for muscles and blood. The proposed method indicates a robust and reliable alternative to other MR-AC approaches targeting patient specific quantitative analysis in time-of-flight PET/MR.

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Questions regarding the nature and strength of noncovalent interactions formed by organic fluorine atoms are increasingly being addressed and debated in the literature.[1] We have been exploring noncovalent interactions of fluorine by carrying out a systematic fluorine scan [2] at the active site of thrombin.[3] While exploring the hydrophobic D pocket of this serine protease, we noticed that the potency of a closely related family of fluorinated inhibitors was strongly influenced by the position of the fluorine atom (Figure 1).[3a] The 4-fluorobenzyl derivative (AE )-4 exhibits fivefold better inhibition than any other member of the family. The X-ray structure of the (+)-4-enzyme complex showed two close contacts between the fluorine atom and the C a ÀH atom as well as the carbonyl C atom of Asn98 (Figure 1 b). Subsequent searches in the Cambridge Structural Database and RCSB Protein Data Bank provided numerous examples of similar sub van der Waals contacts between organic fluorine atoms and carbonyl carbon atoms in chemical and biological samples. These interactions have a characteristic geometry: the fluorine atom tends to reside orthogonally above the pseudotrigonal axis of the carbonyl group, and the C À F bond approaches the plane of the carbonyl group from an angle between 1008 and, at very short F···C distances, 1408.[3a]Herein we report the first model system to evaluate the energetics of the proposed C À F···amide interactions.The distinct geometry of the orthogonal CÀF···amide interaction presented an unusual challenge. We found an answer in the "molecular torsion balance" derived by Wilcox et al. from the Tröger base-a system designed for the accurate measurement of edge-to-face aromatic-aromatic interactions by the observation of a simple conformational equilibrium.[4] We found through examination of existing crystal structures [5] that appropriate substitution of the Tröger base skeleton would provide the perpendicular arrangement of functional groups required for our study (Scheme 1). The use of a trifluoromethyl group was required to approximate the optimal C À F···amide geometry. Based on the similarity of the results obtained from database searches for fluorine atoms attached to sp 2 -and sp 3 -hybridized carbon atoms, we anticipated that this substitution would have a negligible effect on the energetics of the proposed interaction.The second challenge in characterizing fluorine-amide interactions is their expected weakness. The relative K i values for compounds (AE )-1-(AE )-7 suggest that the fluorine substitution provides approximately 4 kJ mol À1 of stabilizing energy. Hunter and co-workers have popularized chemical double-mutant cycles for the measurement of very small interaction energies in supramolecular systems, and have used this method to accurately measure various noncovalent interactions as weak as 1 kJ mol À1 .[6] The application of this strategy to the Wilcox torsion balance is straightforward. The edge-to-face aromatic-aromatic interaction is the primary force behind the folding ...