PMID- 30998730 OWN - NLM STAT- MEDLINE DCOM- 20200107 LR - 20200309 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 14 IP - 4 DP - 2019 TI - In silico analysis of the V66M variant of human BDNF in psychiatric disorders: An approach to precision medicine. PG - e0215508 LID - 10.1371/journal.pone.0215508 [doi] LID - e0215508 AB - 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. FAU - De Oliveira, Clara Carolina Silva AU - De Oliveira CCS AD - Department of Genetics and Molecular Biology, Bioinformatics and Computational Biology Laboratory, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Pereira, Gabriel Rodrigues Coutinho AU - Pereira GRC AD - Department of Genetics and Molecular Biology, Bioinformatics and Computational Biology Laboratory, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Rio de Janeiro, Brazil. FAU - De Alcantara, Jamile Yvis Santos AU - De Alcantara JYS AD - Department of Genetics and Molecular Biology, Bioinformatics and Computational Biology Laboratory, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Antunes, Deborah AU - Antunes D AUID- ORCID: 0000-0002-2927-0800 AD - Computational Biophysics and Molecular Modeling Group, Scientific Computing Program (PROCC), Fundacao Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil. FAU - Caffarena, Ernesto Raul AU - Caffarena ER AD - Computational Biophysics and Molecular Modeling Group, Scientific Computing Program (PROCC), Fundacao Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil. FAU - De Mesquita, Joelma Freire AU - De Mesquita JF AUID- ORCID: 0000-0003-1684-3830 AD - Department of Genetics and Molecular Biology, Bioinformatics and Computational Biology Laboratory, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Rio de Janeiro, Brazil. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190418 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 7171WSG8A2 (BDNF protein, human) SB - IM MH - Amino Acid Substitution MH - *Brain-Derived Neurotrophic Factor/chemistry/genetics MH - *Computer Simulation MH - Female MH - Humans MH - Male MH - Mental Disorders/*genetics MH - *Models, Molecular MH - *Mutation, Missense MH - *Precision Medicine MH - Structure-Activity Relationship PMC - PMC6472887 COIS- NVIDIA's GPU Grant Program recently donated (1) Titan X Pascal GPU for our research group. This donation is an unrestricted gift to support our research efforts and comes at no charge. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials. EDAT- 2019/04/19 06:00 MHDA- 2020/01/08 06:00 PMCR- 2019/04/18 CRDT- 2019/04/19 06:00 PHST- 2018/01/17 00:00 [received] PHST- 2019/04/04 00:00 [accepted] PHST- 2019/04/19 06:00 [entrez] PHST- 2019/04/19 06:00 [pubmed] PHST- 2020/01/08 06:00 [medline] PHST- 2019/04/18 00:00 [pmc-release] AID - PONE-D-18-01778 [pii] AID - 10.1371/journal.pone.0215508 [doi] PST - epublish SO - PLoS One. 2019 Apr 18;14(4):e0215508. doi: 10.1371/journal.pone.0215508. eCollection 2019.