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J Mol Model. 2016 Jan;22(1):14. doi: 10.1007/s00894-015-2868-x. Epub 2015 Dec 17.

Structural signatures of DRD4 mutants revealed using molecular dynamics simulations: Implications for drug targeting.

Author information

1
Bioinformatics Infrastructure Facility, Sri Venkateswara College (University of Delhi), Benito Juarez Road, Dhaula Kuan, New Delhi, 110 021, India.
2
CSIR-Institute of Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110020, India.
3
CSIR-Institute of Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110020, India. lipi.thukral@igib.in.
4
Bioinformatics Infrastructure Facility, Sri Venkateswara College (University of Delhi), Benito Juarez Road, Dhaula Kuan, New Delhi, 110 021, India. lata@bic-svc.ac.in.

Abstract

Human Dopamine Receptor D4 (DRD4) orchestrates several neurological functions and represents a target for many psychological disorders. Here, we examined two rare variants in DRD4; V194G and R237L, which elicit functional alterations leading to disruption of ligand binding and G protein coupling, respectively. Using atomistic molecular dynamics (MD) simulations, we provide in-depth analysis to reveal structural signatures of wild and mutant complexes with their bound agonist and antagonist ligands. We constructed intra-protein network graphs to discriminate the global conformational changes induced by mutations. The simulations also allowed us to elucidate the local side-chain dynamical variations in ligand-bound mutant receptors. The data suggest that the mutation in transmembrane V (V194G) drastically disrupts the organization of ligand binding site and causes disorder in the native helical arrangement. Interestingly, the R237L mutation leads to significant rewiring of side-chain contacts in the intracellular loop 3 (site of mutation) and also affects the distant transmembrane topology. Additionally, these mutations lead to compact ICL3 region compared to the wild type, indicating that the receptor would be inaccessible for G protein coupling. Our findings thus reveal unreported structural determinants of the mutated DRD4 receptor and provide a robust framework for design of effective novel drugs.

KEYWORDS:

GPCR; Intra-protein network; Ligand binding; Molecular dynamics simulations; Mutations

PMID:
26680992
DOI:
10.1007/s00894-015-2868-x
[Indexed for MEDLINE]

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