Calculated conformational

We have previously calculated conformational free energy differences for a well-suited model system, the catalytic subunit of cAMP-dependent protein kinase (cAPK), which is the best characterized member of the protein kinase family. It has been crystallized in three different conformations and our main focus was on how ligand binding shifts the equilibrium among these ([Helms and McCammon 1997]). As an example using state-of-the-art computational techniques, we summarize the main conclusions of this study and discuss a variety of methods that may be used to extend this study into the dynamic regime of protein domain motion. 

I. Pettersson, T. Liljefors, Molecular mechanics calculated conformational energies of organic molecules a comparison of force fields, in Reviews in Computational Chemistry, Vbl. 9,... 

Since the summation in Eq. (12) may be on any subset of atoms, it can be fine-tuned to best suit the problem at hand. The summation may be over the whole molecule, but it is very common to calculate conformational distances based only on non-hydrogen heavy atoms or, in the case of proteins, even based on only the backbone Ca atoms. Alternatively, in a study related to drug design one may consider, for example, focusing only on atoms that make up the pharmacophore region or that are otherwise known to be functionally important. 

Fig. 8.3 Calculated conformational energy display values less than 2kcalmol ligands penalties of the protein-bound ligands 1-36. with five to eight rotors display values less The energy penalty increases with the number than 4kcalmol and ligands with eight to 11 of rotors. Ligands with one to four rotors rotors display values less than 6kcal mol. ...

Cornell, W. D. Cieplak, P. Bayly, C. I. Kollman, P. A., Application of RESP charges to calculate conformational energies, hydrogen bond energies, and free energies of solvation, J. Am. Chem. Soc. 1993,115, 9620-9631. 

The problem of the preferred conformation of cyclodecane has been extensively studied by Dunitz et al. (46). In the crystals of seven simple cyclodecane derivatives (mono- or 1,6-disubstituted cyclodecanes) the same conformation was found for the ten-membered ring (BCB-conformation, Fig. 9). It follows from this that the BCB-conformation is an energetically favourable conformation, possibly the most favourable one. Numerous force field calculations support this interpretation Of all calculated conformations BOB corresponded to the lowest potential energy minimum. Lately this picture has become more complicated, however. A recent force field calculation of Schleyer etal. (21) yielded for a conformation termed TCCC a potential energy lower by 0.6 kcal mole-1 than for BCB. (Fig. 9 T stands for twisted TCCC is a C2h-symmetric crown-conformation which can be derived from rrans-decalin by breaking the central CC-bond and keeping the symmetry.) A force field of... 

Fig. 17. Calculated conformations (top and side views, drawn to scale) of cyclohexane (force field of ref. (79) outer values bond lengths in A and angles in degrees, inner values torsion angles). The quantities below the symmetry symbols are calculated A V- and AH-values (kcal mole-1 T = 298 K reference chair conformation)...

Secondly, as a measure of nonlinearity, the calculation conforms more closely to that concept than the correlation coefficient does. As a contrast, we can consider terms such as precision and accuracy, where high precision and high accuracy mean data with small values of standard deviation> while low precision and low accuracy mean large values of the measure. Thus, for those two characteristics, the measured value changes in opposition to the concept. If we were to use the correlation coefficient calculation as the measure of nonlinearity, we would have the same situation. However, by defining the linearity calculation the way did, the calculation now runs parallel to the concept a calculated value of zero means no nonlinearity while increasing values of the calculation corresponds to increasing nonlinearity. 

Ingrid Pettersson and Tommy Liljefors, Molecular Mechanics Calculated Conformational Energies of Organic Molecules A Comparison of Force Fields. 

J. M. Wang, P. Cieplak, and P. A. Kollmann, How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules J. Comput. Chem. 21, 1049 1074 (2000). 

The internal flexibility of oligosaccharides is a major obstacle to interpretation of experimental data. To deduce three-dimensional structure, one must, therefore, be able to correctly model internal flexibility. Various methods and results for conformational energy calculations for oligosaccharides have recently been reviewed (9-13). Therefore, no attempt will be made here to describe such efforts to calculate conformational energy surfaces. 

The EFF calculations yielded a single Cs-symmetric conformation for each type of ferrichrome analog (Figure 4), both with a A-cis configuration of the hydroxamates about the metal when L-amino acids were used. Taken together with the spectroscopic data, pronounced differences were observed for the conformations of these iron complexes. Inspection of the calculated conformations showed that the backbone amide groups may... 

Figure 7.6 Calculated conformations of aldehydes 28, 29, 32, and 33. Dot lines on 29 and 33 indicate hydrogen bondings and arrows show the approach trajectory of nucleophile.

Calculated conformations, bond lengths, and bond angles which reproduce correctly the experimental values have shown that compound 7 is planar while molecules 8 and 9 show different degrees of nonplanarity (Table 1) <1997JST(413)1>. 

Using Approximate Equilibrium Geometries to Calculate Conformational Energy Differences... 

Pettersson, 1. and Liljefors, T. 1996. Molecular Mechanics Calculated Conformational Energies of Organic Molecules A Comparison of Force Fields , in Reviews in Computational Chemistry, Vol. 9, Lipkowitz, K. B. and Boyd, D. B., Eds., VCH New York, 167. 

Techniques used to calculate conformational energies are NR for "no relaxation", PR for "partialrelaxation", and FR for "fullrelaxation". 

Approximate conformational energy estimates are utilized to evaluate the RIS model of PVDF, Occasional 10-20%) head to head tail to tail (H-H T-T) addition of monomer units in a random fashion is accounted for In the calculation of these conformational properties. In general it is found that the calculated conformational properties are relatively insensitive to the amount of H-H T-T addition assumed, but are instead markedly dependent upon the value of the dielectric constant Is) selected to mediate the electrostatic interactions encountered along a PVDF chain. 

Conformational energies are calculated for chain segments in poly(vlnyl bromide) (PVB) homopolymer and the copolymers of vinyl bromide (VBS and ethylene (E), PEVB. Semlempirical potential functions are used to account for the nonbonded van der Waals and electrostatic Interactions. RIS models are developed for PVB and PEVB from the calculated conformational energies. Dimensions and dipole moments are calculated for PVB and PEVB using their RIS models, where the effects of stereosequence and comonomer sequence are explicitly considered. It is concluded from the calculated dimensions and dipole moments that the dipole moments are most sensitive to the microstructure of PVB homopolymers and PEVB copolymers and may provide an experimental means for their structural characterization. 

The possible backbone phosphodiester conformations in a dinucleotide monophosphate and a dinucleotide triphosphate are investigated by semiempirical energy calculations. Conformational energies are computed as a function of the rotations o and <0 about the internucleotide P-0(3 ) and P-015 1 linkages, with the nucleotide residues themselves assumed to be in one of the preferred [C(3 )-e/K/o) conformations. 

One of the present authors has extensively used the dipole-moment method to calculate conformational equilibria of saturated heterocycles. In hindsight this has been a frustrating experience not so much because of the assumptions and approximations that must be made, but because the results in some cases are in good agreement with those derived from other methods, whereas for other groups of compounds the dipole-moment conclusions are clearly incorrect. In this discussion we first discuss the method, using piperidines as an example, and then attempt to assess its areas of applicability and causes of failure. 

Calculated Conformational Free Energies" and the Proportion of the a Anomer in Aqueous Equilibrium Solution of Aldopyranoses... 

---