I. Introduction to Conformation Searching

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4II. Conformation Searching MethodsSystematic MethodsSystematic conformation searching is a method used to find stable conformers of relatively small molecules. In thismethod, all the flexible torsional angles in the molecule are varied in a systematic fashion in order to generate a setof initial structures. Each initial structure is then energy minimized and the stable conformations are enumerated.The advantage of a systematic search is that all the global and local minima will be found as long as the step-size inthe torsional angle is not too large. However, systematic methods are very difficult to apply to molecules with morethan 7 or 8 flexible torsional angles because the number of initial structures generated becomes enormous and theamount of CPU time to energy minimize each becomes prohibitive.The “difficulty” of a systematic search can be related to the number of structures to be energy minimized. For linearacyclic systems, the difficulty is 6 Nt , where N t is the number of flexible torsions present. A list of calculateddifficulties is presented in Table 2.Table 2. Difficulties of systematic searches involving acyclic systems.Length of Chain Number of Flexible Difficulty(Atoms)Torsions, N t5 2 366 3 2167 4 12968 5 77769 6 46,65610 7 280,00011 8 1,680,00012 9 1.0×10 7: : :17 14 7.8×10 10For cyclic systems, the difficulty is 6 Nt –5Nr , where N t is the number of flexible torsions present and N r is thenumber of rings. A list of calculated difficulties for cyclic systems is presented in Table 3 for N r =1.Table 3. Difficulties of systematic searches involving cyclic systems with one ring.Size of Ring Number of Flexible Difficulty(Atoms)Torsions, N t5 5 16 6 67 7 368 8 2169 9 129610 10 777611 11 46,65612 12 280,000: : :17 17 2.2×10 9
5Monte Carlo MethodsMonte Carlo conformation searching methods are used to find stable conformers of large molecules for whichsystematic searches are not feasible. A Monte Carlo search can be performed by randomly varying the Cartesiancoordinates of a molecule or by randomly varying selected dihedral angles. In these methods, a new structure isgenerated by either shifting the Cartesian coordinates of the atoms by a random amount or by varying the dihedralangles by a random amount. A flow chart for these procedures is shown in Figure 6.Figure 6. Flow chart for Monte Carlo conformation search (from Molecular Modelling:Principles and Applications, 2 nd edition. A. R. Leach, Prentice Hall, Harlow, England, 2001.)Monte Carlo methods that involve randomly varying the cartesian coordinates of a molecule are sometimes referredto as cartesian stochastic searches. An example of one step in such a procedure is shown in Figure 7.Figure 7. The process for a cartesian stochastic search.
Page 2 and 3: 2(a)(b)Figure 2. Potential energy s
Page 6: 6Example: CycloheptadecaneThe objec

I. Introduction to Conformation Searching

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