title: A rational free energy-based approach to understanding and targeting disease-causing missense mutations.
abstract: BACKGROUND
  Intellectual disability is a condition characterized by significant limitations in cognitive abilities and social/behavioral adaptive skills and is an important reason for pediatric, neurologic, and genetic referrals. Approximately 10% of protein-encoding genes on the X chromosome are implicated in intellectual disability, and the corresponding intellectual disability is termed X-linked ID (XLID). Although few mutations and a small number of families have been identified and XLID is rare, collectively the impact of XLID is significant because patients usually are unable to fully participate in society.
  
  
  OBJECTIVE
  To reveal the molecular mechanisms of various intellectual disabilities and to suggest small molecules which by binding to the malfunctioning protein can reduce unwanted effects.
  
  
  METHODS
  Using various in silico methods we reveal the molecular mechanism of XLID in cases involving proteins with known 3D structure. The 3D structures were used to predict the effect of disease-causing missense mutations on the folding free energy, conformational dynamics, hydrogen bond network and, if appropriate, protein-protein binding free energy.
  
  
  RESULTS
  It is shown that the vast majority of XLID mutation sites are outside the active pocket and are accessible from the water phase, thus providing the opportunity to alter their effect by binding appropriate small molecules in the vicinity of the mutation site.
  
  
  CONCLUSIONS
  This observation is used to demonstrate, computationally and experimentally, that a particular condition, Snyder-Robinson syndrome caused by the G56S spermine synthase mutation, might be ameliorated by small molecule binding.
authors: Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, South Carolina 29634, USA.
authors: Zhe
authors: Z
authors: Zhang
authors: Shawn
authors: S
authors: Witham
authors: Marharita
authors: M
authors: Petukh
authors: Gautier
authors: G
authors: Moroy
authors: Maria
authors: M
authors: Miteva
authors: Yoshihiko
authors: Y
authors: Ikeguchi
authors: Emil
authors: E
authors: Alexov
mesh_terms: D001665:Binding Sites; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics; D018118:Chloride Channels / Q000235:genetics; D019295:Computational Biology; D003401:Creatine / Q000172:deficiency / Q000235:genetics; D050172:Genes, X-Linked; D006801:Humans; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000628:therapy; D020125:Mutation, Missense; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000172:deficiency / Q000235:genetics; D011485:Protein Binding / Q000502:physiology; D020836:Protein Structure, Quaternary; D013097:Spermine Synthase / Q000235:genetics* / Q000378:metabolism; D057170:Translational Research, Biomedical
chemical_list: C108828:CLIC2 protein, human; D018118:Chloride Channels; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D013097:Spermine Synthase; D003401:Creatine
keywords: Experimenatal Measurements; In Silico Modeling; Mental Disorders; Missense Mutation; Small Molecule Screening