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

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

Publication date: Jan 17, 2018

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.

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De Oliveira, C.C.S., Pereira, G.R.C., De Alcantara, J.Y.S., Antunes, D., Caffarena, E.R., and De Mesquita, J.F. In silico analysis of the V66M variant of human BDNF in psychiatric disorders: An approach to precision medicine. 04435. 2018 PLoS One (14):4.

Concepts Keywords
3D 3D algorithms
Amyloid Mutation
BDNF Brain-derived neurotrophic factor
Chaperone Developmental neuroscience
Determinant Branches of biology
Hydrogen Bonding 3D algorithms
Intracellular
Molecular Dynamics
Mutation
Neurogenesis
Precision Medicine
Protein
Psychiatric Disorders
Rosetta
SIFT
Synapse

Semantics

Type Source Name
gene UNIPROT CLU
drug DRUGBANK Warfarin
gene UNIPROT AOC1
gene UNIPROT KCNIP1
drug DRUGBANK Ademetionine
drug DRUGBANK Troleandomycin
gene UNIPROT PMP22
gene UNIPROT PXMP2
gene UNIPROT INTU
gene UNIPROT GZMB
gene UNIPROT ACTA1
gene UNIPROT DNASE1L3
drug DRUGBANK Lysergic acid diethylamide
gene UNIPROT APC
gene UNIPROT AIP
gene UNIPROT AURKAIP1
disease DOID AIP
drug DRUGBANK Coenzyme M
disease MESH multi
gene UNIPROT FOXD3
gene UNIPROT UBXN11
gene UNIPROT PROC
gene UNIPROT CASP12
gene UNIPROT SLC6A7
gene UNIPROT BRD2
disease MESH point mutations
disease MESH genetic diseases
gene UNIPROT SOD3
disease DOID Amyotrophic Lateral Sclerosis
disease MESH Amyotrophic Lateral Sclerosis
gene UNIPROT SOD1
gene UNIPROT GLS2
gene UNIPROT ADAM11
gene UNIPROT CCL22
drug DRUGBANK BK-MDA
gene UNIPROT TNIP1
gene UNIPROT HNRNPA1
disease DOID Amyotrophic Lateral Sclerosis 20
gene UNIPROT STUB1
gene UNIPROT BANK1
disease DOID Rett syndrome
disease MESH Rett syndrome
gene UNIPROT GAK
gene UNIPROT GTF2IRD1
gene UNIPROT ERBB2
gene UNIPROT NEU1
gene UNIPROT NEURL1
gene UNIPROT BEST1
gene UNIPROT CPSF4
gene UNIPROT ALPI
gene UNIPROT ALPP
gene UNIPROT POR
disease MESH suicide
gene UNIPROT ELL
disease MESH Men
gene UNIPROT F11R
disease MESH mental disorders
gene UNIPROT RAB34
gene UNIPROT ITSN1
gene UNIPROT GEN1
gene UNIPROT RASA1
gene UNIPROT RGS6
gene UNIPROT EMD
gene UNIPROT TMEM245
disease MESH bends
drug DRUGBANK Gold
drug DRUGBANK L-Cysteine
gene UNIPROT TECR
gene UNIPROT CNTN3
gene UNIPROT CLDN10
gene UNIPROT ARSA
drug DRUGBANK Acetylsalicylic acid
gene UNIPROT FBN1
gene UNIPROT KRT17
gene UNIPROT PCSK2
gene UNIPROT KRT6B
gene UNIPROT CBX4
gene UNIPROT PKD2
gene UNIPROT KRT16
gene UNIPROT PCSK1
gene UNIPROT PKD1
gene UNIPROT PLEKHG5
gene UNIPROT RORC
gene UNIPROT FANCC
gene UNIPROT NR1H4
gene UNIPROT ADRB2
gene UNIPROT BFAR
gene UNIPROT WLS
gene UNIPROT TBATA
gene UNIPROT SLC25A4
gene UNIPROT SLC25A6
gene UNIPROT GUCY2C
gene UNIPROT STAR
gene UNIPROT DYRK3
gene UNIPROT IK
gene UNIPROT TNFSF14
gene UNIPROT INA
drug DRUGBANK Amino acids
disease MESH multiple
gene UNIPROT GPI
drug DRUGBANK Aspartame
gene UNIPROT DEPP1
gene UNIPROT GOPC
drug DRUGBANK Pentaerythritol tetranitrate
gene UNIPROT ARNT
gene UNIPROT MIA3
gene UNIPROT GIMAP8
gene UNIPROT FLVCR1
drug DRUGBANK Pidolic Acid
disease DOID PCA
gene UNIPROT SELENOP
gene UNIPROT MMEL1
gene UNIPROT PLXNB1
gene UNIPROT CSTB
disease DOID PME
gene UNIPROT DUOXA1
drug DRUGBANK Water
disease MESH Visual
gene UNIPROT INS
gene UNIPROT CD48
gene UNIPROT SNAP25
gene UNIPROT PDC
disease MESH development
gene UNIPROT MENT
drug DRUGBANK Trestolone
drug DRUGBANK Titanium
gene UNIPROT RAB35
gene UNIPROT SH3YL1
disease MESH learning disabilities
disease DOID anxiety
disease MESH anxiety
disease DOID obsessive compulsive disorder
disease MESH obsessive compulsive disorder
disease MESH depression
disease DOID bipolar disorder
disease MESH bipolar disorder
pathway BSID Release
drug DRUGBANK Methionine
drug DRUGBANK L-Valine
gene UNIPROT CTNND1
gene UNIPROT CSE1L
gene UNIPROT BCAR1
gene UNIPROT TNFRSF1B
gene UNIPROT TCF3
gene UNIPROT HCLS1
gene UNIPROT SIGLEC7
gene UNIPROT KHSRP
gene UNIPROT CUX1
gene UNIPROT PSIP1
gene UNIPROT NTRK1
gene UNIPROT TPM3
pathway BSID Brain derived neurotrophic factor
disease MESH abnormalities
disease DOID cancer
disease MESH cancer
disease MESH cardiovascular diseases
disease MESH syndromes
gene UNIPROT ZNF746
gene UNIPROT CCS
gene UNIPROT TNFSF13
gene UNIPROT ANP32B
gene UNIPROT FANCE
gene UNIPROT ELOVL6
disease DOID face
gene UNIPROT ABCC8
gene UNIPROT RAMAC
gene UNIPROT RAB27A
gene UNIPROT SYNM
gene UNIPROT FYN
drug DRUGBANK Ribostamycin
gene UNIPROT BDNF

Original Article

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