In silico analysis of the V66M variant of human BDNF in psychiatric disorders: An approach to precision medicine

PLoS One. 2019 Apr 18;14(4):e0215508. doi: 10.1371/journal.pone.0215508. eCollection 2019.

Abstract

Brain-derived neurotrophic factor (BDNF) plays an important role in neurogenesis and synapse formation. The V66M is the most prevalent BDNF mutation in humans and impairs the function and distribution of BDNF. This mutation is related to several psychiatric disorders. The pro-region of BDNF, particularly position 66 and its adjacent residues, are determinant for the intracellular sorting and activity-dependent secretion of BDNF. However, it has not yet been fully elucidated. The present study aims to analyze the effects of the V66M mutation on BDNF structure and function. Here, we applied nine algorithms, including SIFT and PolyPhen-2, for functional and stability prediction of the V66M mutation. The complete theoretical model of BNDF was generated by Rosetta and validated by PROCHECK, RAMPAGE, ProSa, QMEAN and Verify-3D algorithms. Structural alignment was performed using TM-align. Phylogenetic analysis was performed using the ConSurf server. Molecular dynamics (MD) simulations were performed and analyzed using the GROMACS 2018.2 package. The V66M mutation was predicted as deleterious by PolyPhen-2 and SIFT in addition to being predicted as destabilizing by I-Mutant. According to SNPeffect, the V66M mutation does not affect protein aggregation, amyloid propensity, and chaperone binding. The complete theoretical structure of BDNF proved to be a reliable model. Phylogenetic analysis indicated that the V66M mutation of BDNF occurs at a non-conserved position of the protein. MD analyses indicated that the V66M mutation does not affect the BDNF flexibility and surface-to-volume ratio, but affects the BDNF essential motions, hydrogen-bonding and secondary structure particularly at its pre and pro-domain, which are crucial for its activity and distribution. Thus, considering that these parameters are determinant for protein interactions and, consequently, protein function; the alterations observed throughout the MD analyses may be related to the functional impairment of BDNF upon V66M mutation, as well as its involvement in psychiatric disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Brain-Derived Neurotrophic Factor* / chemistry
  • Brain-Derived Neurotrophic Factor* / genetics
  • Computer Simulation*
  • Female
  • Humans
  • Male
  • Mental Disorders / genetics*
  • Models, Molecular*
  • Mutation, Missense*
  • Precision Medicine*
  • Structure-Activity Relationship

Substances

  • Brain-Derived Neurotrophic Factor
  • BDNF protein, human

Grants and funding

This work was supported by FAPERJ - Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (http://www.faperj.br/) FINEP - Financiadora de Estudos e Projetos (http://www.finep.gov.br/) CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (http://www.capes.gov.br/), and CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico (http://cnpq.br/) to CCSDO. We gratefully acknowledge the support of NVIDIA Corporation with their donation of the Titan X Pascal GPU used for this research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.