BACKGROUND Leishmanolysins have been described as important parasite virulence factors because of their roles in the infection of promastigotes and resistance to host’s defenses. Leishmania (Viannia) braziliensis contains several leishmanolysin genes in its genome, especially in chromosome 10. However, the functional impact of such diversity is not understood, but may be attributed partially to the lack of structural data for proteins from this parasite. OBJECTIVES This works aims to compare leishmanolysin sequences from L. (V.) braziliensis and to understand how the diversity impacts in their structural and dynamic features. METHODS Leishmanolysin sequences were retrieved from GeneDB. Subsequently, 3D models were built using comparative modeling methods and their dynamical behavior was studied using molecular dynamic simulations. FINDINGS We identified three subgroups of leishmanolysins according to sequence variations. These differences directly affect the electrostatic properties of leishmanolysins and the geometry of their active sites. We identified two levels of structural heterogeneity that might be related to the ability of promastigotes to interact with a broad range of substrates. MAIN CONCLUSION Altogether, the structural plasticity of leishmanolysins may constitute an important evolutionary adaptation rarely explored when considering the virulence of L. (V.) braziliensis parasites.

A integrina VLA-4 (integrina α4β1) participa da fisiopatologia de uma grande variedade de doenças, incluindo asma, esclerose múltipla, artrite reumatóide e diabetes. A seletividade de ligantes por essa integrina permanece ainda um problema sem resposta, principalmente devido ao fato das estruturas 3D da maioria delas serem ainda desconhecida. Inicialmente, construímos um modelo computacional tridimensional do sítio ativo da integrina α4β1, utilizando a estrutura cristalográfica da integrina αVβ3 como molde. Após, realizamos um estudo por docking molecular usando um conjunto de sete antagonistas de α4β1 derivados de 4-[N'-(2-metilfenil)ureido]fenilacetil, avaliando os seus modos de ligação. A técnica de dinâmica molecular foi utilizada de modo a aumentar a eficiência da exploração do perfil energético obtido pelo algoritmo de docking. Segundo a nossa análise, os compostos foram sistematicamente agrupados em dois modos de ligação principais, sendo a conformação estendida o modo prevalente de ligação dos antagonistas no sítio. Cálculos de energia livre também confirmaram essa constatação. Esse estudo aumenta a compreensão dos mecanismos de ligação dessa família de antagonistas e pode fornecer informações úteis ao desenho racional de fármacos específicos para o VLA-4.

The VLA-4 antigen (α4β1 integrin) is involved in the pathophysiology of a variety of diseases including asthma, multiple sclerosis, rheumatoid arthritis and diabetes. The ligand selectivity toward this integrin remains a difficult problem, mainly due to the fact that 3D structures of most integrins are still unknown. We initially built a 3D computational model of the α4β1 ligand binding site, taking the crystal structure of the integrin αVβ3 as template. Then, we performed a computational study on a set of seven α4β1 antagonists, evaluating the binding modes of 4-[N'-(2-methylphenyl)ureido]phenylacetyl and derivatives by molecular docking. Molecular dynamics simulations were used to improve the receptor-ligand energy landscape exploration by the docking algorithm. The compounds were systematically arranged in two main binding modes, and in all cases, pointed out that these antagonists preferably bind to the α4β1 integrin active site in an extended conformation that resembles the one in solution. LIE (linear interaction energy) calculations also confirmed this statement given that the most prevailing binding mode is also the energetically most favored one. This study benefits the comprehension of the mechanism of this family of antagonists and may provide useful information for rational drug design.