MelanoMD

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Contents

General Information

  • Application's name: MelanoMD
  • Application's acronym: NAMD
  • Scientific domain: Computational Chemistry
  • Contact person: Adina Milac, amilac<>biochim.ro
  • Main Developers: Adina Milac,Institute of Biochemistry of the Romanian Academy/Department of Bioinformatics and Structural Biochemistry
  • Co-developers: Gabriela Negroiu, Andrei Petrescu
  • Allocation period: 01/05/2013-31/07/2013
  • Web site:

Objectives of the computing project

Obtain trajectories of molecular dynamics simulations of the transmembrane (TM) segment in several melanogenic enzymesanalyse, the interaction of TM segment with the surrounding lipid environment, comparative analysis of the TM segment stability between several melanogenic enzymesanalyse, the influence of cholesterol on the TM segment stability.

Application's description

Melanosomal proteins members of the Tyrosinase-Related Proteins (TRP) family are controlling different steps in the synthesis of melanic pigment, being the only enzymes well-acknowledged so far to modulate the amounts and qualities of melanin pigment. They are type I membrane proteins, with an N-terminal catalytic domain in the cytoplasmic side of the membrane, followed by a transmembrane segment of variable length and hydrophobicity and a C-terminal extracellular short domain.

Malignant melanoma (MM) is a type of neoplasm resulted from the transformation and proliferation of melanocytes, the cells responsible for the production of melanic pigment. Cutaneous MM is ranked 8th amongst the common types of cancers and it is one of the most insidious types of cancer. In the context of malignant transformation of melanocytes, TRPs are both Diagnostic Markers and Therapeutic Targets, therefore a thorough understanding of their structure and function is crucial for their use as clinical targets. Despite high sequence homology among TRPs, experimental results in our institute indicate that they display different trafficking pathways between ER and Golgi and different responses to cholesterol-blocking agents such as Nystatin, methyl betacyclodextrins.

Molecular dynamics simulations of TM segments of the two investigated TRPs embedded in lipid bilayers, both in the presence and absence of cholesterol, will be used to understand the structural basis for the differences in stability and membrane affinity between the two proteins. Our study is important for its clinical applications in melanoma diagnosis and treatment, but it also valuable from the computational point of view, since it is one of the very few simulation studies focused on TM type I proteins and the importance of membrane cholesterol levels for protein stability and trafficking.

Results expected in the allocation period

- Molecular dynamics trajectories of two different TRPs embedded in pure POPC membrane and cholesterol-containing POPC membrane.

- Analysis of the structural stability of the TM segment in the membrane

- Understand the role of cholesterol in the interaction of TM segment with membrane and its consequences on protein trafficking

- Analysis of the sequence patterns that influence stability and interaction with cholesterol

Activity report

  • Adina-Luminita Milac, Petruta Alexandru, Marioara Marin, Carmen Tanase, Gabriela Negroiu, "Cholesterol effects on stability and intracellular processing of melanosomal membrane proteins", presented at the 9th European Biophysics Congress EBSA2013, 13-17 July 2013, Lisbon.
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