Structure prediction flexible molecules

As discussed in several places in this chapter, when predicting the crystal structures of flexible molecules, intra- and intermolecular energies must be optimized together. 

Ouvrard, C., Price, S.L., 2004, Toward Crystal Structure Prediction for Conformationally Flexible Molecules The Headaches Illustrated by Asprin, Crystal Growth and Design, Vol.4, No. 6, 1119-1127. 

Fig. 11 The giant flexible molecule proposed as one of the six targets in the last crystal structure prediction blindfold test...

Controversial discussions have surrounded the three-dimensional structure of flexible dendrimers in solution during the past two decades. Now, on the basis of numerous SANS experiments using the contrast variation technique, the idea that isolated flexible dendrimers in good solvents do not take on the originally predicted dense shell structure but instead assume a dense core structure [47] appears to be gaining general acceptance. This means that in such dendrimers the segment density reaches a maximum at the centre of the molecule and decreases towards the periphery (cf. Fig. 7.6). 

Rigid Molecule Group theory will be given in the main part of this paper. For example, synunetry adapted potential energy function for internal molecular large amplitude motions will be deduced. Symmetry eigenvectors which factorize the Hamiltonian matrix in boxes will be derived. In the last section, applications to problems of physical interest will be forwarded. For example, conformational dependencies of molecular parameters as a function of temperature will be determined. Selection rules, as wdl as, torsional far infrared spectrum band structure calculations will be predicted. Finally, the torsional band structures of electronic spectra of flexible molecules will be presented. 

Diffusion requires cooperative motions of both the polymer and the diffusant [27] and is therefore only low below T , and severely restricted below Tg. The diffusion of various stabilizers was elucidated in amorphous and semicrystalline polymers and in multiphase systems. In semicrystalline polymers, diffusion takes place almost exclusively in the amorphous phase and the value of D is sensitive to the total crystallinity and the morphology. It is difficult to predict D within a homologuous series of stabilizers. For a given molecular weight, long and flexible molecules diffuse more rapidly than more rigid and compact structures. For a given stabilizer, the value of D is usually lower in PP and HDPE than in LDPE. It was demonstrated that typical AO molecules have a very restricted mobility in polymers. They are, however, insufficient experimental data to correlate the AO mobility and the AO efficiency. 

Mooij, W.T.M. van Eijck, B.P. Kroon, J. Ab initio crystal structure predictions for flexible hydrogen-bonded molecules. J. Am. Chem. Soc. 2000, 122, 3500-3505. 

Since many critical physical and mechanical properties of pharmaceutical compounds are in large part dependent on crystal form, accurate prediction of crystal structure would be a highly valued tool in the pharmaceutical industry. Unfortunately, to date, reliable crystal structure prediction is only feasible for rigid, low molecular weight molecules, which do not represent the size and flexibility of pharmaceutical molecules. 

Methods for searching the conformational space of small and medium-sized molecules have been reviewed [969]. A general problem in the prediction of 3D structures of flexible drugs is the fact that conformations in vacuo i.e. all conformations calculated by force field, semiempirical, or ab initio methods) may be significantly different from the conformations in aqueous solution (2D NMR... 

---