Distance geometry and molecular dynamics

TF Flavel. Predicting the structure of the fiavodoxm from Eschericia coli by homology modeling, distance geometry and molecular dynamics. Mol Simul 10 175-210, 1993. 

I. de Vlief and W. F. van Gunsteren. Combined procedures of distance geometry and molecular dynamics for detenmmng protein structure from nuclear m iFtics resonance data. Methods En ymol 202 268-300 (1991). 

A comparison of various methods for searching conformational space has been performed for cycloheptadecane (C17H34) [Saunders et al. 1990]. The methods compared were the systematic search, random search (both Cartesian and torsional), distance geometry and molecular dynamics. The number of unique minimum energy conformations found with each method within 3 kcal/mol of the global minimum after 30 days of computer processing were determined (the study was performed in 1990 on what would now be considered a very slow computer). The results are shown in Table 9.1. 

G. M. Crippen, Distance Geometry and Conformational Calculations , Wiley, Chichester, England, 1981 G. M. Crippen, T. F. HaveL Distance Geometry and Molecular Dynamics , John Wiley Sons, New York, Chichester, Brisbane, Toronto, Singapore, 1988. 

Ensemble Distance Geometry, Ensemble Molecular Dynamics and Genetic Algorithms... 

Finally, Burkhard Luy, Andreas Frank and Horst Kessler discuss Conformational Analysis of Drugs by Nuclear Magnetic Resonance Spectroscopy . The determination and refinement of molecular conformations comprehends three main methods distance geometry (DG), molecular dynamics (MD) and simulated anneahng (SA). In principle, it is possible to exclusively make use of DG, MD or... 

Greater accuracy can be achieved by methods that involve calculation of a full relaxation matrix from the NOESY data to generate interproton distances. A model protein structure can then be iteratively refined by back calculation until differences in the empirical and calculated data are minimized. The resulting distances can be used as restraints for further refining the protein structure by distance geometry or molecular dynamics methods. 

Given all inter-residue contacts or distances (Figure 1), 3D structure can be reconstructed by distance geometry or molecular dynamics. This is used for the determination of 3D structures by NMR spectroscopy which produces experimental data of distances between protons. Can inter-residue contacts be predicted Obviously, some fraction of these contacts can be helices and strands can be assigned based on hydrogen-bonding pattern between residues. Thus, a successful prediction of secondary structure implies a successful prediction of some fraction of all the contacts. However, contacts predicted from secondary structure assignment are... 

The greatest value of molecular dynamic simulations is that they complement and help to explain existing data for designing new experiments. The simulations are increasingly useful for structural refinement of models generated from NMR, distance geometry, and X-ray data. 

H. Pepermans, D. Tourwe, G. van Binst, R. Boelens, R. M. Scheek, W. F. van Gunsteren, and R. Kaptein, Biopolymers, 27,323 (1988). The Combined Use of NMR, Distance Geometry and Restrained Molecular Dynamics for the Conformational Study of a Cyclic Somatostatin Analogue. 

G. M. Clore, M. Nilges, D. K. Sukumaran, A. T. Briinger, M. Karplus, and A. M. Gronen-born, EMBO J., 5, 2729 (1986). The Three-Dimensional Structure of a-Purothionin in Solution Combined Use of Nuclear Magnetic Resonance, Distance Geometry, and Restrained Molecular Dynamics. 

Distance geometry provides sets of 3-D structures of a protein or nucleic acid that fulfill the constraints. The combination of distance geometry, for generation of molecular starting points, with molecular dynamics computations can yield 3-D models of small proteins with precision equal to X-ray crystallography. This combination of NMR, molecular mechanics, and molecular dynamics can be used to provide a three-dimensional protein structure in a situation where the protein cannot be crystallized or the crystals are not appropriate for X-ray crystallography. 

DHFR catalyzes the reduction of 7,8-dihydrofolate (H2F) to 5,6,7,8-tetrahydrofolate (H4F) using nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor (Fig. 17.1). Specifically, the pro-R hydride of NADPH is transferred stereospecifi-cally to the C6 of the pterin nucleus with concurrent protonation at the N5 position [1]. Structural studies of DHFR bound with substrates or substrate analogs have revealed the location and orientation of H2F, NADPH and the mechanistically important side chains [2]. Proper alignment of H2F and NADPH is crucial in enhancing the rate of the chemical step (hydride transfer). Ab initio, mixed quantum mechanical/molecular mechanical (QM/MM), and molecular dynamics computational studies have modeled the hydride transfer process and have deduced optimal geometries for the reaction [3-6]. The optimal C-C distance between the C4 of NADPH and C6 of H2F was calculated to be 2.7A [5, 6], which is significantly smaller than the initial distance of 3.34 A inferred from X-ray crystallography [2]. One proposed chemical mechanism involves a keto-enol tautomerization (Fig. 

---