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Described is a new National Institutes of Health supported Molecular Biology Computer Research Resource located at the Dana-Farber Cancer Institute in association with Harvard University, Boston, Massachusetts.
Developments in computational methods and equipment have produced a new type of research chemist, who prefers to calculate properties as well as measure them, either to gain a better understanding of microscopic molecular behaviour per se, or to guide a broader scientific study using a so-called 'rational' approach. While there is good reason to believe that significant results can be obtained this way, it is clear that only some of the 'tools of the trade' are sufficiently robust to present to those who are not experts in the field. This paper discusses the underlying basis for molecular modelling techniques, describing their history, state of maturity and prospects for future development. The intention is to outline the scope that these play in an industrial research environment, and to examine how they can successfully be incorporated as routine research tools. Computer-based molecular modelling is not a unique discipline. Some comparisons are drawn between it and other computer-based techniques that have reached a greater degree of maturity, in order to highlight the points made.
The rate of generation of molecular sequence data is forcing the use of computers as a central tool in molecular biology. Current use of computers is limited largely to data management and sequence comparisons, but rapid growth in the volume of data is generating pressure for the development of high-speed analytical methods for deciphering the codes connecting nucleotide sequence with protein structure and function.
Theoretical chemistry, as implemented on fast computers, is beginning to yield accurate predictions of the thermodynamic and kinetic properties of large molecular assemblies. In addition to providing detailed insights into the origins of molecular activity, theoretical calculations can be used to design new molecules with specific properties. This article describes two types of calculations that show special promise as design tools, the thermodynamic cycle-perturbation method and the Brownian reactive dynamics method. These methods can be applied to calculate equilibrium and rate constants that describe many aspects of molecular recognition, stability, and reactivity.
Recent development of solution-phase molecular-scale Boolean calculations using deoxyribozymes is potentially an important step toward the development of autonomous therapeutic and diagnostic devices. Here, the construction of basic YES, AND, ANDNOT, and ANDANDNOT deoxyribozyme-based logic gates is described. Protocols for testing gate activity using fluorescent oligonucleotide probes have been provided, and pointers for gate optimization are included.
A three-dimensional model of human cannabinoid receptor is constructed using computer-aided molecular modeling techniques. The helices of bacteriorhodopsin were used as the initial template to construct the transmembrane helices. The extracellular and intracellular loops were added using the SYBYL molecular modeling package. The extracellular N terminus was modeled on the basis of its similarity to rat oncomodulin. Similarly, the C terminus was constructed on the basis of similarity to bovine prothrombin fragment 1. The final structure was refined by several runs of minimization and dynamics calculation using the CHARMm package. delta 9-Tetra hydrocannabinol was docked into the internal cavity using the AUTODOCK program. Our study snows that there may be a calcium-binding site in the extracellular N terminus of this receptor. The ligand binds mainly to a hydrophobic site, which consists of residues Met-240, Trp-241 (TMH-4), Trp-356, Leu-359, Leu-360 (TMH-6), and Ala-283 (TMH-5). Its phenolic hydroxyl group forms a hydrogen bond with the carboxy group of Ala-198 (TMH-3). The results of modeling agree well with experimental QSAR studies.
Computer-aided molecular modeling of the antibody binding site of eight different monoclonal antibodies (mAb) that bind the intense sweetener ligand (N-(p-cyanophenyl)-N'-diphenylmethyl) guanidine acetic acid was completed using canonical loop structures and framework regions from known immunoglobulins as "parent structures" for the molecular scaffoldings. The models of the fragment variable (Fv) region of the mAb were analyzed for the presence and location of residues predicted to be involved in ligand binding. Several binding site tryptophan residues in these models were located in positions that support previous flurospectroscopic observations of the mAb-ligand complexation. Computer-aided renderings of the electrostatic potential at the van der Waals surface of the Fv region were compared and found to be consistent with the ligand binding specificity profiles for the different mAb. The Fv model of mAb NC6.8 was consistent with the binding site features determined in the Fab structure recently solved by X-ray diffraction techniques. These Fv models should provide an adequate basis for site-directed mutagenesis experiments in order to characterize interactive motifs in the mAb binding site.
The amorphous aluminum silicate (Al2O3)2(SiO2) [AS2] is investigated by means of large scale molecular dynamics computer simulations. We consider fully equilibrated melts in the temperature range 6100 K> or =T> or =2300 K as well as glass configurations that were obtained from cooling runs from T=2300 to 300 K with a cooling rate of about 10(12) K/s. Already at temperatures as high as 4000 K, most of the Al and Si atoms are fourfold coordinated by oxygen atoms. Thus, the structure of AS2 is that of a disordered tetrahedral network. The packing of AlO4 tetrahedra is very different from that of SiO4 tetrahedra in that Al is involved with a relatively high probability in small-membered rings and in triclusters in which an O atom is surrounded by four cations. We find as typical configurations two-membered rings with two Al atoms in which the shared O atoms form a tricluster. On larger length scales, the system shows a microphase separation in which the Al-rich network structure percolates through the SiO2 network. The latter structure gives rise to a prepeak in the static structure factor at a wave number q=0.5 A(-1). A comparison of experimental x-ray data with the results from the simulation shows good agreement for the structure function. The diffusion dynamics in AS2 is found to be much faster than in SiO2. We show that the self-diffusion constants for O and Al are very similar and that they are by a factor of 2-3 larger than the one for Si.
A number of relatively low-cost processors are now available which employ architectural features previously found only on very expensive supercomputers. The speed of these computers makes it possible to reduce the time to solution of certain problems and to resolve large problems that previously were too time consuming to perform locally. A brief overview of this type of processor is given and the implications for computations in molecular biophysics are discussed in reference to the results of a benchmark that uses the refinement of a protein structure from X-ray crystallographic data.
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The interaction of DNA with the polyamine spermine(4+) (Spm(4+)), sodium ions, and water molecules has been studied using molecular dynamics computer simulations in a system modeling a DNA crystal. The simulation model consisted of three B-DNA decamers in a periodic hexagonal cell, containing 1200 water molecules, 8 Spm(4+), 32 Na(+), and 4 Cl(-) ions. The present paper gives a more detailed account of a recently published report of this system and compares results on this mixed Spm(4+)/Na(+)-cation system with an molecular dynamics simulation carried out for the same DNA decamer under similar conditions with only sodium counterions (Korolev et al., J. Mol. Biol. 308:907). The presence of Spm(4+) makes significant influence on the DNA hydration and on the interaction of the sodium ions with DNA. Spermine pushes water molecules out of the minor groove, whereas Na(+) attracts and organizes water around DNA. The major binding site of the Spm(4+) amino groups and the Na(+) ions is the phosphate group of DNA. The flexible polyamine spermine displays a high presence in the minor groove but does not form long-lived and structurally defined complexes. Sodium ions compete with Spm(4+) for binding to the DNA bases in the minor groove. Sodium ions also have several strong binding sites in the major groove. The ability of water molecules, Spm(4+), and Na(+) to modulate the local structure of the DNA double helix is discussed.
We review our recent work on the direct calculation of the interfacial free energy, gamma, of the crystal-melt interface via molecular dynamics computer simulation for a number of model systems. The value of gamma as a function of crystal orientation is determined using a thermodynamic integration technique employing moving cleaving walls [Phys. Rev. Lett. 2000, 85, 4751]. The calculation is sufficiently precise to resolve the small anisotropy in gamma, which is crucial in determining the kinetics and morphology of dendritic growth. We report values of gamma for the hard-sphere and Lennard-Jones systems, as well as recent results on the series of inverse-power potentials. For the inverse sixth-, seventh-, and eighth-power systems, we determine gamma for both fcc and bcc crystal structures. For these systems, the bcc-melt gamma is lower than that for fcc crystals by about 25%, consistent with recent experiments and computer simulations on fcc-forming systems that show preferential formation of bcc nuclei in the initial stages of crystallization. In addition, we show that our results give a molecular interpretation of Turnbull's rule, which is the empirical relationship between gamma and the enthalpy of fusion.
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Three-dimensional (3D) models of the human Gs protein, the human beta 3 adrenergic receptor and their complex are constructed using computer-aided molecular modeling techniques. The structures of bacterial EF-tu 200 and bacteriorhodopsin were used as starting points for modeling the Gs protein and beta 3 receptor, respectively. Experimental data are used as constraints to guide the modeling. The resulting 3D structures of the Gs protein, the beta 3 receptor and their complex are in accord with the experimental data. It is found that the third intracellular loop of the beta 3 receptor as well as its C-terminus are involved in the binding. Various residues of N-terminus and C-terminus of the Gs protein also participate in the binding. The model of the complex suggests that the Gs protein binds to the beta 3 receptor in such a way that it will be placed in the interface of membrane and intracellular space. This orientation is supported by experimental data. It is concluded that the modeled structure of the complex of the alpha subunit of the human Gs protein and the beta 3 adrenergic receptor is in agreement with the experimental data and it can provide a basis for understanding the way these proteins interact.
The theory of artificial neural networks is briefly reviewed focusing on supervised and unsupervised techniques which have great impact on current chemical applications. An introduction to molecular descriptors and representation schemes is given. In addition, worked examples of recent advances in this field are highlighted and pioneering publications are discussed. Applications of several types of artificial neural networks to compound classification, modelling of structure-activity relationships, biological target identification, and feature extraction from biopolymers are presented and compared to other techniques. Advantages and limitations of neural networks for computer-aided molecular design and sequence analysis are discussed.
A three-dimensional model of human cathepsin E, a possible endothelin-converting enzyme, is constructed using computer-aided molecular modeling techniques. The structure of porcine pepsin, another aspartic protease, was used as a template. The final structure, after all gaps and deletions were made, was optimized using the AMBER-4 package. A dipeptide (Trp-Val) representing the substrate was docked in the putative active site and the whole structure was optimized after several runs of minimization and dynamics calculations. The result of this modeling study showed that the structure of cathepsin E is similar to that of porcine pepsin and has three disulfide bonds that are conserved in both enzymes. There are two Asp-Thr-Gly sequences at the active site of enzyme. The active site cavity is large enough to accommodate its substrate.
Monoclonal antibody NC6.8 binds the superpotent sweetener ligand N-(p-cyanophenyl)-N'-(diphenylmethyl) guanidineacetic acid with high affinity (Kd = 53 nM). Using computer-aided molecular modeling and several experimental techniques, such as competitive ligand binding, absorbance spectroscopy, and fluorescence spectroscopy, we have predicted the structure of the variable domain fragment (Fv) and identified the key residues in the combining site of the antibody. We have identified nine specific amino acids as being involved in ligand recognition and complexation. Most notable are H:33W, which is responsible for ligand-induced tryptophan fluorescence quenching, H:56R, which forms a salt bridge with the carboxylate moiety of the ligand, and L:34H, which, deep in the binding site, interacts with the cyanophenyl portion of the ligand. Two residues located deep in the putative binding pocket, H:35E and H:50E, provide the negatively charged potential for interaction with the protonated aryl nitrogen and the positive guanidinium group. These modeling predictions were made before the solution of high-resolution structures of the native Fab (2.6 A) and the Fab-ligand complex (2.2 A). Comparisons between the theoretical model and experimental native and liganded Fab structures are made.
In this paper our main purpose is to give molecular solutions for the subset-product problem. In order to achieve this, we propose three DNA-based algorithms--parallel adder, parallel multiplier and parallel comparator--that formally verify our designed molecular solutions for the subset-product problem. We also show that Boolean circuits are not needed to perform mathematical operations on a molecular computer. Furthermore, this work indicates that the subset-product problem is solved and also presents clear evidence of the ability of molecular computing to perform complicated mathematical operations.