## 1 Introduction  
The GTPase proteins, specifically HRAS, KRAS, and NRAS, function as molecular switches that regulate intracellular signaling pathways in cell growth and differentiation [1; 2; 3]. These RAS proteins share a similar structure and can transition between an active, GTP-bound state and an inactive, GDP-bound state [4; 5; 6; 7; 8]. Numerous studies have shown that mutations in the three RAS proteins are implicated in various human cancers [9; 10; 11], highlighting their distinct roles in exploring potential cancer therapies [12; 13]. Furthermore, these mutations significantly impact the conformational dynamics of RAS proteins, which play a critical role in their interactions with cell signaling proteins [14; 15]. Given their importance in anticancer treatment, considerable attention has been directed towards designing small molecule inhibitors that target allosteric sites on RAS proteins. Additionally, comprehending the conformational dynamics of RAS proteins is crucial for inhibitor development. Therefore, uncovering the molecular mechanisms underlying mutation-induced conformational changes in RAS proteins is essential for advancing effective anti-cancer drugs. Recently, there has been increased attention on HRAS, one of the three RAS proteins (HRAS, KRAS, and NRAS), due to its involvement in mutation-induced oncology activity [16; 17; 18; 19; 20; 21; 22; 23; 24]. HRAS has two switch domains, switch domain 1 (SW1) and switch domain 2 (SW2), as shown in Figure 1A. SW1 consists of residues 28-40, while SW2 is composed of residues 59-75. The switch domains SW1 and SW2 undergo significant changes due to GTP hydrolysis into GDP and point mutations [25; 26; 27; 28]. Experimental structures have revealed that point mutations and ligand bindings cause conformational alterations in the switch domains of HRAS [29; 30; 31; 32; 28]. [PERSON] et al. employed X-ray crystallography, nuclear magnetic resonance spectroscopy, binding assays, and molecular dynamics (MD) simulations to investigate the autophosphorylated mutants of HRAS and KRAS. Their findings suggested that the phosphoryl transfer from GTP requires dynamic movement of the SW2 [33]. [PERSON] et al. determined the experimental structure of the HRAS T35S/GppNHp complex. They found that T35S not only caused noticeable conformational alterations in the switch domains, but also implicated the naphthalene ring as a potential scaffold for developing RAS inhibitors [34]. [PERSON] et al. 's study indicated that oncogenic mutations Q61L and Q61H may disrupt intramolecular structural communication between the switch domains SW1 and SW2 of RAS proteins [35]. [PERSON] et al., using multiple solvent crystal structures and computational solvent mapping (FTMap), explored binding site hot spots in the \"off\" and \"on\" allosteric states of GTP-associated HRAS. Their findings suggested that the global conformational rearrangement of HRAS acts as a mechanism for allosteric coupling between the effector interface and remote hot spots in all RAS isoforms [36]. The aforementioned experimental structures provide valuable information for further investigating the function of HRAS and its potential role in future drug design. Apart from experimental works, various computational technologies have been extensively utilized to elucidate the molecular mechanism of ligand-target identification and investigate ligand-HRAS binding modes. These technologies include MD simulations [37; 38; 39; 40; 41; 42], Gaussian accelerated molecular dynamics (GaMD) simulations [43; 44], calculations of binding free energies [45; 46; 47; 48; 49; 50; 51], and principal component analysis (PCA) [52; 53; 54; 55]. The research conducted by [PERSON]'s group involved MD simulations, binding free energy prediction, and dynamic net  
Figure 1: The structures of HRAS, GTP, and GDP. **(A)** The structure of HRAS is shown in cartoon modes with clear labels indicating the second structures. **(B)** Two mutated sites, A59 and K117, are displayed in surface modes.