Exploring Conformational Space with Thermal Fluctuations Obtained by Normal-Mode Analysis

SALDAÑO, TADEO E.; FREIXAS, VICTOR M.; TOSATTO, SILVIO C. E.; PARISI, GUSTAVO; FERNANDEZ-ALBERTI, SEBASTIAN

JOURNAL OF CHEMICAL INFORMATION AND MODELING

AMER CHEMICAL SOC

Año: 2020

1549-9596

Proteins in their native states can be represented as ensembles of conformers in dynamical equilibrium. Thermal fluctuations are responsible for transitions between these conformers. Normal modes analysis (NMA) using elastic network models (ENM) provides an efficient procedure to explore global dynamics of proteins commonly associated to conformational transitions. In the present work, we present an iterative approach to explore protein conformational spaces by introducing structural distortions according to their equilibrium dynamics at room temperature. The approach can be used either to perform unbiased explorations of conformational space or to explore guided pathways connecting two different conformations, e.g., apo and holo forms. In order to test its performance, four proteins with different magnitude of structural distortions upon ligand binding have been tested. In all cases, the conformational selection model has been confirmed and the conformational space between apo and holo forms has been encompassed. Different strategies have been tested that impact either on the efficiency to achieve a desired conformational change or to achieve a balanced exploration of the protein conformational multiplicity.