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==Unbinding== Substrate unbinding is influenced by various factors. Larger ligands generally stay in the active site longer,<ref name="PanBorhani2013">{{cite journal|last1=Pan|first1=Albert C.|last2=Borhani|first2=David W.|last3=Dror|first3=Ron O.|last4=Shaw|first4=David E.|title=Molecular determinants of drug–receptor binding kinetics|journal=Drug Discovery Today|volume=18|issue=13–14|year=2013|pages=667–673|issn=1359-6446|doi=10.1016/j.drudis.2013.02.007|pmid=23454741}}</ref> as do those with more rotatable bonds (although this may be a side effect of size).<ref name="MillerLunn2012">{{cite journal|last1=Miller|first1=Duncan C.|last2=Lunn|first2=Graham|last3=Jones|first3=Peter|last4=Sabnis|first4=Yogesh|last5=Davies|first5=Nichola L.|last6=Driscoll|first6=Paul|title=Investigation of the effect of molecular properties on the binding kinetics of a ligand to its biological target|journal=MedChemComm|volume=3|issue=4|year=2012|pages=449–452|issn=2040-2503|doi=10.1039/c2md00270a}}</ref> When the solvent is excluded from the active site, less flexible proteins result in longer [[residence time]]s. More hydrogen bonds shielded from the solvent also decrease unbinding.<ref name="PanBorhani2013"/>
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