Notes
Slide Show
Outline
1
Conformational searching
Quench Dynamics
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History
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Protocol for conformational search: quenched molecular dynamics
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Use of conformational search as a tool for structure determination
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Identification of pharmacophores:
The role of simulations
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Recognition of the m-opioid receptor
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Drugs with pharmacophores derived from the fentanyl model for enkephalin peptides
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Conformation of Leu-enkephalin in solution: a study in H2O and DMSO
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Experimental studies of leu-enkephalin do not agree on structure
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Two forms of leu-enkephalin: zwitterionic and neutral
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A stable salt-bridge is formed in both water and DMSO between the ends of the peptide in the zwitterionic form
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Secondary structure in water and DMSO
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Distributions of c angles
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Time-correlation function for c angles
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Time-correlation function for c angles
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The bent form of leu-enkephalin is similar to a cyclized form
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Some cyclic enkephalin peptides show biological activity
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Cyclized a-melanotopins are biologically active
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Distribution of energies
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RMS maps
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Example of a cyclic prodrug of Leu-enkephalin
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ROEs of Leu-enkephalin are used as restraints in conformational search
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Restrained dynamics as a tool in NMR structure determination
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Experimental data can be incorporated into a simulation using a flat-bottomed potential
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Energy distribution for
the cyclic prodrug
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RMS correlation plot for the cyclic prodrug
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What is the free energy of a structure?
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Configurational free energy
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Vibrational entropy can be calculated for each structure to give an entropic contribution to the free energy
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Conclusion