João Martins

Publications (3) View all

• Article: Understanding the importance of the aromatic amino-acid residues as hot-spots.

  I S Moreira, J M Martins, R M Ramos, P A Fernandes, M J Ramos
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  ABSTRACT: Protein-protein interactions (PPI) are crucial for the establishment of life. However, its basic principles are still elusive and the recognition process is yet to be understood. It is important to look at the biomolecular structural space as a whole, in order to understand the principles behind conformation-function relationships. Since the application of an alanine scanning mutagenesis (ASM) study to the growth hormone it was demonstrated that only a small subset of residues at a protein-protein interface is essential for binding - the hot-spots (HS). Aromatic residues are some of the most typical HS at a protein-protein interface. To investigate the structural role of the interfacial aromatic residues in protein-protein interactions, we performed Molecular Dynamic (MD) simulations of protein-protein complexes in a water environment and calculated a variety of physical-chemical characteristics. ASM studies of single residues and of dimers or high-order clusters were performed to check for cooperativity within aromatic residues. Major differences were found between the behavior of non-HS aromatic residues and HS aromatic residues that can be used to design drugs to block the critical interactions or to predict major interactions at protein-protein complexes.
  Biochimica et Biophysica Acta 07/2012; · 4.66 Impact Factor
• Article: Structural Determinants of a Typical Leucine-Rich Repeat Protein

  Joao M. Martins, Rui M. Ramos, Irina S. Moreira
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  ABSTRACT: The structural and functional description of protein-protein complexes and their comprehension is a key concept, not only to increase the scientific knowledge in basic terms but also for the application to the biomedical and pharmaceutical industry. The binding association between proteins is nowadays attribute to a few key residues at the interface - the hot-spots. The complex between the RNase inhibitor (RI) and RNaseA protein provides an excellent system to study the role of the functional epitope as it is essential in various molecular recognition processes and constitute one of the tightest complexes known. An energetic pattern of the interface is accomplished by computational alanine scanning mutagenesis and a dynamical characterization is accomplished by a detailed study of the molecular dynamical simulations. A special emphasis is given to the role of solvation across the interface and the shielding of warm- and hot-spots from water.
  Communications in Computational Physics 06/2012; 13(1):238-255. · 1.40 Impact Factor
• Article: Are hot-spots occluded from water?

  Irina Sousa Moreira, Rui Miguel Ramos, Joao Miguel Martins, Pedro Alexandrino Fernandes, Maria João Ramos
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  ABSTRACT: Protein-protein interactions are the basis of many biological processes and are governed by focused regions with high binding affinities, the warm- and hot-spots. It was proposed that these regions are surrounded by areas with higher packing density leading to solvent exclusion around them - "the O-ring theory." This important inference still lacks sufficient demonstration. We have used Molecular Dynamics (MD) simulations to investigate the validity of the O-ring theory in the context of the conformational flexibility of the proteins, which is critical for function, in general, and for interaction with water, in particular. The MD results were analyzed for a variety of solvent-accessible surface area (SASA) features, radial distribution functions (RDFs), protein-water distances, and water residence times. The measurement of the average solvent-accessible surface area features for the warm- and hot-spots and the null-spots, as well as data for corresponding RDFs, identify distinct properties for these two sets of residues. Warm- and hot-spots are found to be occluded from the solvent. However, it has to be borne in mind that water-mediated interactions have significant power to construct an extensive and strongly bonded interface. We observed that warm- and hot-spots tend to form hydrogen bond (H-bond) networks with water molecules that have an occupancy around 90%. This study provides strong evidence in support of the O-ring theory and the results show that hot-spots are indeed protected from the bulk solvent. Nevertheless, the warm- and hot-spots still make water-mediated contacts, which are also important for protein-protein binding.
  Journal of biomolecular structure & dynamics 02/2013; · 4.99 Impact Factor