In this work, we systematically analyzed aspects of a previously proposed MD-based protein structure refinement protocol. The main outcome is a new optimized protocol that showed significant improvements over previous MD simulation-based refinement protocols with improved accuracy and a wider range of applicability of structure refinement to targets of larger size and with poorer initial model quality. There are three components that were essential for the improvements: 1) A combined use of Cartesian restraints and inter-residue distances based on Cα atoms led to better balance between preserving and improving both global and local structures; 2) The use of elevated temperatures during simulation (i.e. 360 K) allowed more productive accelerated sampling towards native-like conformation without unfolding due to the presence of restraints; 3) The use of alternative initial models that were generated via hybridization of the initial model with additional template-based models resulted in better refinement performance due to an expanded the conformational space and access to alternative models that may be more refinable in different parts of a given structure compared to the initial model. The new protocol brings refined structures significantly closer to experimental accuracy and expands the practical application of MD-based refinement methods.