Molecular dynamics simulations are pivotal in elucidating the intricate properties of biological molecules. Nonetheless, the reliability of their outcomes hinges on the precision of the molecular force field utilized. In this perspective, we present a comprehensive review of the developmental trajectory of the Amber additive protein force field, delving into researchers’ persistent quest for higher precision force fields and the prevailing challenges. We detail the parameterization process of the Amber protein force fields, emphasizing the specific improvements and retained features in each version compared to their predecessors. Furthermore, we discuss the challenges that current force fields encounter in balancing the interactions of protein–protein, protein–water, and water–water in molecular dynamics simulations, as well as potential solutions to overcome these issues.
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