CAMSEQ

N. Conformational Analysis of Molecules in Solution (CAMSEQ). A problem of long standing in chemistry has been to estimate the relationship between the conformation of a molecule in the crystal, as measured by X-ray methods, with that in solution where barriers to rotation are greatly reduced. A sophisticated program set for Conformational Analysis of Molecules in Solution by Empirical and Quantum-mechanical methods (CAMSEQ) has been developed for this purpose by Hopfinger and co-workers [l2] at Case Western Reserve University. 

This program, in its interactive version, can be run in under 20K words of core and CAMSEQ has recently been added to the CIS as part of the X-ray system described in section C of this chapter. 

Structure building, manipulation. Rigid conformational searching with interface to CAMSEQ/PC. Stick, ball-and-stick, and space-filling display. PC. 

CAMSEQ/M A Microprocessor-Based Conformational Analysis System... 

Conformational analysis is becoming a widely utilized tool in drug design, molecular modeling, and the determination of structure-activity relationships. Of the many techniques presently available for conformational studies, classical, empirical potential energy functions hold great promise in providing relatively inexpensive explorations of conformational hyperspace in various simulated solvent environments. An excellent example of the application of these classical techniques is embodied in the CAMSEQ Software System (1,2.,3.). 

The availability of such a system which also provided interactive graphics capability prompted the development of "CAMSEQ/M". 

Atom Types "Built-in" to the CAMSEQ/M Potential Functions... 

Solvation effects are an important aspect of conformational studies involving biologically important molecules. CAMSEQ/M utilizes a modified hydration shell model to account for these environmental effects (3,9,11,15). Several simulated solvent environments may be calculated. These include aqueous, 1-octanol... 

The preceeding discussion has briefly described the potential functions and geometry determination algorithms employed in CAMSEQ and particularly in CAMSEQ/M. The "batch" version of CAMSEQ currently in use is totally compatible with CAMSEQ/M. CAMSEQ/M can be interfaced (via a communications link) to a host computer for more lengthy calculations where speed is a requirement (rather than economy). 

The availability of microprocessor-based interactive computer graphics devices and rapid access disk storage has provided the CAMSEQ/M system with many of the features of the NIH-EPA-CIS (on a smaller scale, of course) and in addition, provides "no-cost", local computational facilities. 

In practice, it is rarely necessary to maintain hundreds of diverse molecular structures for immediate access. Conformational studies are generally performed on a small congeneric series of molecules which, of course, should be immediately available. CAMSEQ/M provides for the local storage of several hundred structures. If additional structures are required, the NIH-EPA-CIS can be linked to the local terminal via telephone... 

CAMSEQ/M was developed around a Tektronix 4051 Microcomputer Graphics System. The hardware required includes the basic 4051 microcomputer with a minimum of 16k bytes of memory (32k is recommended), a "joystick" graphical input device, and a matrix function package (in a read-only memory firmware pack). A vastly more versatile system requires the addition of a file manager/ disk system. In order to communicate with the NIH-EPA-CIS or another "host" computer, a communications interface is necessary. The total hardware cost is approximately 17,000. Table II outlines the required hardware. The 4051 utilizes a direct view storage display which does not employ a selective erase feature. Therefore, it is necessary to replot the screen frequently in order to remove unwanted information. This handicap is the price one must pay for low cost, but quite sophisticated computer graphics features, and does not pose any major problems in CAMSEQ/M. 

Upon turning on the system and initiating CAMSEQ/M, the user is shown a "menu" from which to select the particular task to be performed. Figure 1 illustrates the screen display after the "crystallographic coordinate" input feature has been selected. 

As can be seen, the program prompts the user for the various unit cell parameters. At nearly any point, a "question mark" may be typed, and CAMSEQ/M will highlight the appropriate information on the screen to assist the user in determining what he should do. 

CAMSEQ/M provides the user with the capability to input complete molecular structures from the internal (disk) data base, to input cartesian or crystallographic coordinates, or to use a "joystick" controlled model-building system. In addition, a molecule may be constructed from one or more substructures with substituents attached using the joystick model-builder routines. Data input is therefore quite flexible, and the user is guided through every step by the program. 

Figure 1. This menu is provided to allow the user to select the appropriate work to be done by CAMSEQ/M in this example, crystallographic coordinate...

Figure 4. Final structure of phenethylamine generated hy CAMSEQ/M from the approximate drawing in Figure 3...

Figure 4 illustrates the "standard" model generated by CAMSEQ/M. This structure may be saved for later use, and/or be used as an input structure for a conformational study. The structure may later be used as a substructure for studying other congeners, by modifying its substituents. For example, amphetamine may easily be constructed by adding the alpha-methyl group to the ethylamine sidechain. The stereochemistry of the molecule is determined by the order of input of the substituents. 

At this stage, the molecular coordinates have been determined, and the structure has been verified for accuracy by inspection of the drawings and tables provided by CAMSEQ/M. The next step involves setting up the desired conformational study to be performed. A well documented procedure has been developed for CAMSEQ/M to assist the user in this often difficult task. 

Since CAMSEQ/M has been designed to be totally compatible with the "batch" versions of CAMSEQ, additional options are provided which are appropriate for that version of the program. 

A total of 50 options are available. The advantage of having total compatibility with the batch CAMSEQ is that CAMSEQ/M may be used either as a "stand-alone" conformational analysis device, or it may be used as an interactive, conversational, off-line input device for batch CAMSEQ. Since an available host computer would probably perform the calculations more rapidly than the Tektronix microcomputer, this provides an easy to use batch program interface when results are needed "immediately". 

Figure 6. CAMSEQ/M provides a brief description of each input item for the selected options. A full description of the option is available by pressing the help key (user key 10 on the Tektronix keyboard) and entering the option name.

Automatic searches of conformational hyperspace may be requested using the multi-level bond rotation algorithm described above. A selection is made for a uniform sequential scan, a random scan, or a multi-dimensional minimization search of the conformational energy surface. (As indicated above, prototype versions of CAMSEQ/M provide only the sequential scan mode.)... 

Based on the options specified, CAMSEQ/M may request additional information regarding the energy parameters to use, the solvent environments to be simulated, and other pertinent information regarding the conformational analysis to be performed. The user is then given the opportunity to assemble a batch CAMSEQ data set to be sent to an alternate computer. This feature assembles all data accumulated into the form of a CAMSEQ run deck and saves the information on a disk file. Alternatively, CAMSEQ/M begins the conformational analysis task, saving rotational and energy information on a disk file. 

Complete conformational analyses may be performed using CAMSEQ/M. The figures in this report were prepared directly from the screen display (produced by a Tektronix hard copy device). Photographs may also be made from the screen display. 

Current efforts in the development of the CAMSEQ/M system include the interfacing of a low-cost microcomputer to the 4051 to handle the actual conformational search and energy calculation. This would free the graphics terminal for other general purpose computing tasks including the set-up of additional molecules for conformational study. Conceptually, banks of these low-cost microcomputers could be linked to a single 4051 to provide a very efficient conformational analysis device. 

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